Substituted diazine and triazine spleen tyrosine kinease (Syk) inhibitors

ABSTRACT

The invention provides certain substituted diazine and triazine compounds of the Formula (I) (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R cy , C y , and t are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2013/046134, filed Jun. 17, 2013,which claims priority under 35 U.S.C. §119(e) from U.S. ProvisionalApplication No. 61/663,048, filed Jun. 22, 2012.

FIELD OF THE INVENTION

The present invention relates to certain substituted diazine andtriazine compounds of the Formula (I) (also referred to herein as the“compounds of the Formula (I)” or “compounds of Formula (I)”) which areinhibitors of Spleen Tyrosine Kinase (Syk) kinase activity. The presentinvention also provides compositions comprising such compounds, andmethods of using such compounds for treating conditions or disordersassociated with inappropriate Syk activity, in particular in thetreatment and prevention of disease states mediated by Syk. Such diseasestates may include inflammatory, allergic and autoimmune diseases, forexample, asthma, chronic obstructive pulmonary disease (COPD), adultrespiratory distress syndrome (ARDS), ulcerative colitis, Crohnsdisease, bronchitis, dermatitis, allergic rhinitis, psoriasis,scleroderma, urticaria, rheumatoid arthritis, idiopathicthrombocytopenic purpura (ITP), multiple sclerosis, cancer, HIV andlupus.

BACKGROUND OF THE INVENTION

Spleen Tyrosine Kinase (Syk) is a protein tyrosine kinase which has beendescribed as a key mediator of immunoreceptor signalling in a host ofinflammatory cells including mast cells, B-cells, macrophages andneutrophils. These immunoreceptors, including Fc receptors and theB-cell receptor, are important for both allergic diseases andantibody-mediated autoimmune diseases and thus pharmacologicallyinterfering with Syk could conceivably treat these disorders.

Allergic rhinitis and asthma are diseases associated withhypersensitivity reactions and inflammatory events involving a multitudeof cell types including mast cells, eosinophils, T cells and dendriticcells. Following exposure to allergen, high affinity immunoglobulinreceptors for IgE and IgG become cross-linked and activate downstreamprocesses in mast cells and other cell types leading to the release ofpro-inflammatory mediators and airway spasmogens. In the mast cell, forexample, IgE receptor cross-linking by allergen leads to release ofmediators including histamine from pre-formed granules, as well as thesynthesis and release of newly synthesized lipid mediators includingprostaglandins and leukotrienes.

Syk kinase is a non-receptor linked tyrosine kinase which is importantin transducing the downstream cellular signals associated withcross-linking Fc_(epsilon)RI and or Fc_(epsilon)RI receptors, and ispositioned early in the signalling cascade. In mast cells, for example,the early sequence of Fc_(epsilon)RI signalling following allergencross-linking of receptor-IgE complexes involves first Lyn (a Src familytyrosine kinase) and then Syk. Inhibitors of Syk activity wouldtherefore be expected to inhibit all downstream signalling cascadesthereby alleviating the immediate allergic response and adverse eventsinitiated by the release of pro-inflammatory mediators and spasmogens(Wong et al. 2004, Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).

Recently, it has been shown that the Syk kinase inhibitor R112 (Rigel),dosed intranasally in a phase I/II study for the treatment of allergicrhinitis, gave a statistically significant decrease in PGD₂, a keyimmune mediator that is highly correlated with improvements in allergicrhinorrhea, as well as being safe across a range of indicators, thusproviding the first evidence for the clinical safety and efficacy of atopical Syk kinase inhibitor. (Meltzer, Eli O.; Berkowitz, Robert B.;Grossbard, Elliott B, Journal of Allergy and Clinical Immunology (2005),115(4), 791-796). In a more recent phase II clinical trial for allergicrhinitis (Clinical Trials.gov Identifier NCT0015089), R112 was shown ashaving a lack of efficacy versus placebo.

Rheumatoid Arthritis (RA) is an auto-immune disease affectingapproximately 1% of the population. It is characterised by inflammationof articular joints leading to debilitating destruction of bone andcartilage. Recent clinical studies with Rituximab, which causes areversible B cell depletion, (J. C. W. Edwards et al. 2004, New Eng. J.Med. 350: 2572-2581) have shown that targeting B cell function is anappropriate therapeutic strategy in auto-immune diseases such as RA.Clinical benefit correlates with a reduction in auto-reactive antibodies(or Rheumatoid Factor) and these studies suggest that B cell functionand indeed auto-antibody production are central to the ongoing pathologyin the disease.

Studies using cells from mice deficient in the Spleen Tyrosine Kinase(Syk) have demonstrated a non-redundant role of this kinase in B cellfunction. The deficiency in Syk is characterized by a block in B celldevelopment (M. Turner et al. 1995 Nature 379: 298-302 and Cheng et al.1995, Nature 378: 303-306). These studies, along with studies on matureB cells deficient in Syk (Kurasaki et al. 2000, Immunol. Rev.176:19-29), demonstrate that Syk is required for the differentiation andactivation of B cells. Hence, inhibition of Syk in RA patients is likelyto block B cell function, and thereby reduce Rheumatoid Factorproduction. In addition to the role of Syk in B cell function, and offurther relevance to the treatment of RA, is the requirement for Sykactivity in Fc receptor (FcR) signalling. FcR activation by immunecomplexes in RA has been suggested to contribute to the release ofmultiple pro-inflammatory mediators.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that are potentinhibitors of Syk as well as pharmaceutical compositions containingthem. As Syk inhibitors compounds of Formula (I) are useful in thetreatment and prevention of diseases and disorders mediated by the Sykprotein; such diseases and disorders include, but are not limited to,asthma, COPD, rheumatoid arthritis, cancer and idiopathicthrombocytopenic purpura.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred tousing both a chemical structure and a chemical name, and an ambiguityexists between the structure and the name, the structure predominates.These definitions apply regardless of whether a term is used by itselfor in combination with other terms, unless otherwise indicated. Hence,the definition of “alkyl” applies to “alkyl” as well as the “alkyl”portions of “hydroxyalkyl,” “fluoroalkyl,” “—O-alkyl,” etc.

As used herein, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a chimpanzee.

The term “therapeutically effective amount” as used herein, refers to anamount of the compound of Formula (I) and/or an additional therapeuticagent, or a composition thereof that is effective in producing thedesired therapeutic, ameliorative, inhibitory or preventative effectwhen administered to a patient suffering from a disease or conditionmediated by Syk. In the combination therapies of the present invention,a therapeutically effective amount can refer to each individual agent orto the combination as a whole, wherein the amounts of all agentsadministered are together effective, but wherein the component agent ofthe combination may not be present individually in an effective amount.

The term “preventing,” as used herein with respect to cancer or aninflammatory disease or disorder, refers to reducing the likelihood ofcancer pain or an inflammatory disease or disorder.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup having one of its hydrogen atoms replaced with a bond having thespecified number of carbon atoms. In different embodiments, an alkylgroup contains from 1 to 6 carbon atoms (C₁-C₆ alkyl) or from 1 to 3carbon atoms (C₁-C₃ alkyl). Non-limiting examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyland neohexyl. In one embodiment, an alkyl group is linear. In anotherembodiment, an alkyl group is branched.

The term “fluoroalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a fluorine. In one embodiment, a fluoroalkylgroup has from 1 to 6 carbon atoms. In another embodiment, a fluoroalkylgroup has from 1 to 3 carbon atoms. In another embodiment, a fluoroalkylgroup is substituted with from 1 to 3 F atoms. Non-limiting examples offluoroalkyl groups include —CH₂F, —CHF₂, and —CF₃. The term “C₁-C₃fluoroalkyl” refers to a fluoroalkyl group having from 1 to 3 carbonatoms.

The term “alkoxy” as used herein, refers to an —O-alkyl group, whereinan alkyl group is as defined above. Non-limiting examples of alkoxygroups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy andt-butoxy. An alkoxy group is bonded via its oxygen atom to the rest ofthe molecule.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to 10carbon atoms (C₆-C₁₀ aryl). In another embodiment an aryl group isphenyl. Non-limiting examples of aryl groups include phenyl andnaphthyl.

The term “cycloalkyl,” as used herein, refers to a saturated ringcontaining the specified number of ring carbon atoms, and no heteroatom.In a like manner the term “C₃-C₆ cycloalkyl” refers to a saturated ringhaving from 3 to 6 ring carbon atoms. Non-limiting examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “halo,” as used herein, means —F, —Cl, —Br or —I. In oneembodiment, a halo group is —F or —Cl. In another embodiment, a halogroup is —F.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 3 of the ring atoms is independently N, O, or S andthe remaining ring atoms are carbon atoms. In one embodiment, aheteroaryl group has 5 to 10 ring atoms. In another embodiment, aheteroaryl group is monocyclic ring system and has 5 or 6 ring atoms. Inanother embodiment, a heteroaryl group is a bicyclic ring system. Aheteroaryl group is joined via a ring carbon atom. The term “heteroaryl”also includes a heteroaryl as defined above fused to a heterocyclyl asdefined below. The term “heteroaryl” also encompasses a heteroarylgroup, as defined above, which is fused to a benzene, a cyclohexadieneor a cyclohexene ring. Non-limiting examples of heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyrazolyl, furyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, indolyl, quinoxalinyl,phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl,imidazo[2,1-b]thiazolyl, and the like. In one embodiment, a heteroarylgroup is a 5-membered heteroaryl. In another embodiment, a heteroarylgroup is a 6-membered heteroaryl.

The term “heterocyclyl,” as used herein, refers to a non-aromaticsaturated or partially saturated monocyclic or multicyclic ring systemcontaining 3 to 11 ring atoms, wherein from 1 to 4 of the ring atoms areindependently O, S, or N, and the remainder of the ring atoms are carbonatoms. In one embodiment, a heterocyclyl group is monocyclic and hasfrom 3 to 7 ring atoms. In another embodiment, a heterocyclyl group ismonocyclic and has from about 4 to 7 ring atoms. In another embodiment,a heterocyclyl group is bicyclic and has from 7 to 11 ring atoms. Instill another embodiment, a heterocyclyl group is monocyclic and has 5or 6 ring atoms. In one embodiment, a heterocyclyl group is monocyclic.In another embodiment, a heterocyclyl group is bicyclic. A heterocyclylgroup can be joined to the rest of the molecule via a ring carbon orring nitrogen atom. The nitrogen or sulfur atom of the heterocyclyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of monocyclic heterocyclyl ringsinclude oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, dihydropyranyl, pyran, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone,and the like.

In one embodiment, a heterocyclyl group is a 5- to 6-membered monocyclicheterocyclyl. In another embodiment, a heterocyclyl group is a5-membered monocyclic heterocyclyl. In another embodiment, aheterocyclyl group is a 6-membered monocyclic heterocyclyl. The term “5-to 6-membered heterocyclyl” refers to a monocyclic heterocyclyl grouphaving from 5 to 6 ring atoms.

The term “substituted” means that one or more hydrogens on the atoms ofthe designated are replaced with a selection from the indicated group,provided that the atoms' normal valencies under the existingcircumstances are not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When any substituent or variable occurs more than one time in anyconstituent or the compound of Formula (I), its definition on eachoccurrence is independent of its definition at every other occurrence,unless otherwise indicated.

The term “in purified form,” as used herein, refers to the physicalstate of a compound after the compound is isolated from a syntheticprocess (e.g., from a reaction mixture), a natural source, or acombination thereof. The term “in purified form,” also refers to thephysical state of a compound after the compound is obtained from apurification process or processes described herein or well-known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

The compounds of Formula (I) may contain one or more stereogenic centersand can thus occur as racemates, racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. Additionalasymmetric centers may be present depending upon the nature of thevarious substituents on the molecule. Each such asymmetric center willindependently produce two optical isomers and it is intended that all ofthe possible optical isomers and diastereomers in mixtures and as pureor partially purified compounds are included within the ambit of thisinvention. Any formulas, structures or names of compounds described inthis specification that do not specify a particular stereochemistry aremeant to encompass any and all existing isomers as described above andmixtures thereof in any proportion. When stereochemistry is specified,the invention is meant to encompass that particular isomer in pure formor as part of a mixture with other isomers in any proportion.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts andsolvates of the compounds as well as the salts, solvates and esters ofthe prodrugs), such as those which may exist due to asymmetric carbonson various substituents, including enantiomeric forms (which may existeven in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations.

The compounds of Formula (I) can form salts which are also within thescope of this invention. Reference to a compound of Formula (I) hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula (I) contains both a basic moiety, such as, but not limited toa pyridine or imidazole, and an acidic moiety, such as, but not limitedto a carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Such acidic and basicsalts used within the scope of the invention are pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts. Salts ofthe compounds of Formula (I) may be formed, for example, by reacting acompound of Formula (I) with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

The present invention further includes the compounds of Formula (I) inall their isolated forms. For example, the above-identified compoundsare intended to encompass all forms of the compounds such as, anysolvates, hydrates, stereoisomers, and tautomers thereof.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

In the compounds of generic Formula (I), the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula (I). For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within generic Formula (I) can beprepared without undue experimentation by conventional techniques wellknown to those skilled in the art or by processes analogous to thosedescribed in the examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

Compounds of the Invention

The present invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R^(cy), C^(y), and t are as defined below. Described below areembodiments of the compound of Formula (I). The compounds of Formulae(IA) and (IB) are embodiments of the compound of Formula (I). Below aredescribed various embodiments of the compound of Formula (I).

In embodiment no. 1 the present invention provides a compound of theFormula (I): or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is selected from the group consisting of H, C₁-C₃ alkyl,        C₁-C₃ fluoroalkyl, C₁-C₃ alkoxy, and C₃-C₆ cycloalkyl;    -   R² is selected from the group consisting of H, C₁-C₃ alkyl,        C₁-C₃ alkoxy, C₁-C₃ fluoroalkyl, halo, and cyano;    -   R³ is selected from the group consisting of H, C₁-C₃ alkyl and        halo;    -   R⁴ is selected from the group consisting of H, C₁-C₃ alkyl,        —N(R^(4a))₂, —N(R^(4a))C(O)R^(4b), —N(R^(4a))C(O)N(R^(4a))₂,

-   -   -   each R^(4a) is independently selected from the group            consisting of H and C₁-C₃ alkyl;        -   R^(4b) is C₁-C₃ alkyl;

    -   C^(y) is a 6-membered heteroaryl selected from the group        consisting of:

-   -   t is 0, 1, or 2;    -   each R^(cy) is independently selected from the group consisting        of:        -   A. a group of the formula

wherein

-   -   -   -   Y is a bond, —N(R^(e))—, or —O—;                -   R^(e) is H, C₁-C₃ alkyl; hydroxyl(C₂-C₃)alkyl;            -   each R^(a) and R^(b) is independently selected from the                group consisting of H, fluoro, hydroxyl, —CH₂OH,                —CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl;            -   or R^(a) and R^(b) together with the carbon atom to they                are attached form a group of the formula

-   -   -   -   -   wherein R¹¹ is C₁-C₃ alkyl;                -   m is 1, 2, 3, or 4; and                -   r is 0, 1, 2, or 3;

            -   each R^(e) and R^(d) is independently selected from the                group consisting of H, fluoro, hydroxyl, —CH₂OH,                —CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl;

            -   R^(f) is methyl, —CHF₂, —CF₃, —CH₂SO₂—(C₁-C₃)alkyl,                —CH₂—S(O)₂N(R^(h))₂, —CH₂OH, —C(CH₃)₂OH,                —CH₂—O—(C₁-C₃)alkyl, —CO₂R^(g), —CON(R^(h))₂,                —CH₂—N(H)—C(O)—(C₁-C₃)alkyl, or CN;                -   R^(g) is H or C₁-C₃ alkyl;                -   each R^(h) is independently H or C₁-C₃ alkyl;

            -   n1 is 0, 1, 2, or 3; and

            -   n2 is 0 or 1;

        -   B. a group of the formula

wherein

-   -   -   -   D¹ is a 4- to 7-membered heterocyclic ring optionally                containing one additional heteroatom selected from the                group consisting of N, O, S, S(O), and S(O)₂;            -   each R¹⁰ is independently selected from the group                consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, —CO₂H,                —OH, hydroxyl(C₁-C₃)alkyl, —CH₂OCH₃,                -   —C(O)—(C₁-C₃)alkyl, and —CON(R^(h))₂ or wherein when                    two R¹⁰ moieties are geminally substituted on a                    common ring carbon atom of D¹, the two geminally                    substituted R¹⁰ moieties together with the carbon                    atom on which they are attached form —C(O)—; and            -   q is 0, 1, 2, 3, or 4;

        -   C. a group of the formula

wherein

-   -   -   -   D² is selected from the group consisting of:                -   (i) a C₅-C₆ cycloalkyl,                -   (ii) a 5- to 6-membered heterocyclyl containing 1 or                    2 heteroatoms selected from the group consisting of                    N, O, S, S(O), and S(O)₂;                -   (iii) a 5- to 6-membered heteroaryl containing 1 to                    2 heteroatoms selected from the group consisting of                    N, O, and S; and                -   (iv) phenyl;            -   each R^(i) and R^(j) is independently H or C₁-C₃ alkyl;            -   s is 0, 1, 2, or 3; and            -   Y, R¹⁰ and q are as described above.

In embodiment no. 2, R¹ is trifluoromethyl and the remaining variablesare as described in embodiment no. 1.

In embodiment no. 3, R⁴ is selected from the group consisting of H andC₁-C₃ alkyl, and the remaining variables are as described in any one ofembodiment nos. 1 and 2.

In embodiment no. 4, R⁴ is methyl, and the remaining variables are asdescribed in any one of embodiment nos. 1 and 2.

In embodiment no. 5, R² and R³ are both H, and the remaining variablesare as described in any one of embodiment nos. 1-4.

In embodiment no. 6, C^(y) is selected from the group consisting of

and the remaining variables are as described in any one of embodimentnos. 1-5.

In embodiment no. 7, C^(y) is

and the remaining variables are as described in any one of embodimentnos. 1-5.

In embodiment no. 8, t is 0 or 1, and the remaining variables are asdescribed in any one of embodiment nos. 1-7.

In embodiment no. 9, t is 1, and the remaining variables are asdescribed in any one of embodiment nos. 1-7.

In embodiment no. 10, R^(cy) is a group of the formula

wherein

-   -   Y is a bond, —N(R^(e))—, or —O—;        -   R^(e) is H, C₁-C₃ alkyl; hydroxyl(C₂-C₃)alkyl;    -   each R^(a) and R^(b) is independently selected from the group        consisting of H, fluoro, hydroxyl, —CH₂OH, —CH₂—O—(C₁-C₃)alkyl,        and C₁-C₃ alkyl;    -   or R^(a) and R^(b) together with the carbon atom to they are        attached form a group of the formula

-   -   -   wherein R¹¹ is C₁-C₃ alkyl;        -   m is 1, 2, 3, or 4; and        -   r is 0, 1, 2, or 3;

    -   each R^(e) and R^(d) is independently selected from the group        consisting of H, fluoro, hydroxyl, —CH₂OH, —CH₂—O—(C₁-C₃)alkyl,        and C₁-C₃ alkyl;

    -   R^(f) is methyl, —CHF₂, —CF₃, —CH₂SO₂—(C₁-C₃)alkyl,        -   —CH₂—S(O)₂N(R^(h))₂, —CH₂OH, —C(CH₃)₂OH,            —CH₂—O—(C₁-C₃)alkyl, —CO₂R^(g), —CON(R^(h))₂,            —CH₂—N(H)—C(O)—(C₁-C₃)alkyl, or CN;            -   R^(g) is H or C₁-C₃ alkyl;            -   each R^(h) is independently H or C₁-C₃ alkyl;        -   n1 is 0, 1, 2, or 3;        -   n2 is 0 or 1; and            the remaining variables are as described in any one of            embodiment nos. 1-9.

In embodiment no. 11, R^(cy) is as described in embodiment no. 10,wherein

each R^(a) and R^(b) is independently selected from the group consistingof H, fluoro, hydroxyl, —CH₂OH, —CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl;

each R^(e) and R^(d) is independently selected from the group consistingof H, fluoro, hydroxyl, —CH₂OH, —CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl;and

and the remaining variables are as described in any one of embodimentnos. 1-9.

In embodiment no. 12, R^(cy) is as described in embodiment no. 10,wherein

-   -   Y is —N(R^(e))—;    -   R^(e) is H or methyl;    -   each R^(a), R^(b), R^(e), and R^(d) is independently H, C₁-C₃        alkyl, hydroxyl, —CH₂OH, or —CH₂—O—CH₃;    -   R^(f) is —CO₂H;    -   n1 is 1 or 2;    -   n2 is 0 or 1; and        the remaining variables are as described in any one of        embodiment nos. 1-9.

In embodiment no. 13, R^(cy) is a group of the formula

R^(e), R^(f), R¹¹, m, and r are as described in embodiment no. 10, andthe remaining variables are described in any one embodiments nos. 1-9.

In embodiment no. 14, R^(cy) is as described in embodiment no. 13,wherein r is 0, and the remaining variables are as described in any oneof embodiment nos. 1-9.

In embodiment no. 15,

-   -   R^(cy) is a group of the formula

wherein

-   -   -   D¹ is a 4- to 7-membered heterocyclic ring optionally            containing one additional heteroatom selected from the group            consisting of N, O, S, S(O), and S(O)₂;        -   each R¹⁰ is independently selected from the group consisting            of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, —CO₂H, —OH,            hydroxyl(C₁-C₃)alkyl, —CH₂OCH₃,            -   —C(O)—(C₁-C₃)alkyl, and —CON(R^(b))₂ or wherein when two                R¹⁰ moieties are geminally substituted on a common ring                carbon atom of D¹, the two geminally substituted R¹⁰                moieties together with the carbon atom on which they are                attached form —C(O)—;        -   q is 0, 1, 2, 3, or 4; and            the remaining variables are as described in any one of            embodiment nos. 1-9.

In embodiment no. 16,

R^(cy) is selected from the group consisting of:

-   -   wherein p1 is 1, 2, or 3;    -   p2 is 1 or 2;    -   q is 0 or 1; and        the remaining variables are as described in any one of        embodiment nos. 1-9.

In embodiment no. 17,

-   -   R^(cy) is

wherein

-   -   p1 is 1 or 2;    -   q is 1; and    -   R¹⁰ is —CO₂H; and        the remaining variables are as described in any one of        embodiment nos. 1-9.

In embodiment no. 18,

R^(cy) is a group of the formula a group of the formula

wherein

-   -   D² is selected from the group consisting of:        -   (i) a C₅-C₆ cycloalkyl,        -   (ii) a 5- to 6-membered heterocyclyl containing 1 or 2            heteroatoms selected from the group consisting of N, O, S,            S(O), and S(O)₂;        -   (v) a 5- to 6-membered heteroaryl containing 1 to 2            heteroatoms selected from the group consisting of N, O, and            S; and        -   (vi) phenyl;    -   each R^(i) and R^(j) is independently H or C₁-C₃ alkyl;    -   s is 0, 1, 2, or 3; and        Y, R^(i), R¹⁰, s, q are as described in embodiment no. 1, and        the remaining variables are as described in any one of        embodiment nos. 1-9.

In embodiment no. 19, R^(cy) is selected from the group consisting of:

-   -   q is 0, 1, or 2;        R¹⁰ and the remaining variables are as described in in any one        of embodiment nos. 1-9.

In embodiment no. 20, R^(cy) is selected from the group consisting of:

andthe remaining variables are as described in in any one of embodimentnos. 1-9.

In embodiment no. 21, Y is a bond or —N(R^(e))—, wherein R^(e) is H, andthe remaining variables are as described in any one embodiment nos.18-20.

In embodiment no. 22, the compound of the Formula (I) has the Formula(IA)

and R^(cy) is as described in any one of embodiment nos. 1 and 10-21.

In embodiment no. 23, the compound has the Formula (IA) as set forth inembodiment no. 22, and R^(cy) is as described in embodiment nos. 12, 13,14, or 17.

In embodiment no. 24, the compound of the Formula (I) has the Formula(IB)

and R^(cy) is as described in any one of embodiment nos. 1 and 10-21.

In embodiment, no. 25, the compound has the Formula (IB) as set forth inembodiment no. 24, and R^(cy) is

wherein R^(i) and R^(j) are independently H or C₁-C₃ alkyl;

-   -   R¹⁰ is C₁-C₃ alkyl; and    -   q is 0, 1, or 2.

In embodiment no. 26, the compound is selected from the group consistingof:

-   N-(3-methyl-5-pyrimidin-5-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   N-[3-(2-methoxypyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   N-[3-(2-aminopyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   N-(3-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoic    acid;-   ethyl    3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoate;-   ethyl    3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-2-yl)propanoate;-   ethyl    3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoate;-   2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,3-diol;-   2-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]alanine;-   1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxylic    acid;-   1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclobutanecarboxylic    acid;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]proline;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]azetidine-2-carboxylic    acid-   3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}pyrrolidin-2-one;-   N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta-alanine;-   N-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]alanine;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]pyrrolidin-3-ol;-   4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butanoic    acid;-   N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycine;-   3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,2-diol;-   N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]norvaline;-   1,1-difluoro-3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-2-ol;-   N-(3-{2-[(1,1-dioxidotetrahydrothiophen-3-yl)amino]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   N-[3-methyl-5-(2-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   N-{3-methyl-5-[2-(tetrahydrofuran-3-ylamino)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine;-   N-(3-{2-[(1,4-dioxan-2-ylmethyl)amino]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   N-{3-[2-(1,1-dioxidothiomorpholin-4-yl)pyrimidin-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine;-   N-(3-methyl-5-{2-[(1-pyridin-2-ylethyl)amino]pyrimidin-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   5-({[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}methyl)pyrrolidin-2-one;-   2-{4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]morpholin-2-yl}ethanol;-   4-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-1,4-diazepan-5-one;-   N-(3-{2-[2-(methoxymethyl)morpholin-4-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}ethanesulfonamide;-   3-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidin-3-ol;-   3-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]pyrrolidin-3-ol;-   4-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidin-4-ol;-   2-{methyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}ethanol;-   2,2′-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]imino}diethanol;-   N-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycine;-   N-[3-(2-{[2-(1H-imidazol-4-yl)ethyl]amino}pyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-1-ol;-   4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butan-1-ol;-   (1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopentyl)methanol;-   N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycinamide;-   O-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]serine;-   N-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta-alaninamide;-   N-{3-[2-(4-acetylpiperazin-1-yl)pyrimidin-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine;-   N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]serine;-   3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}azepan-2-one;-   3-{methyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,2-diol;-   N-methyl-N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycinamide;-   N-[2-(1,3-dioxolan-2-yl)ethyl]-N-methyl-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-amine;-   4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperazin-2-one;-   2-methyl-1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-2-ol;-   N-[3-methyl-5-(2-{[2-(methylsulfonyl)ethyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   N-(3-{2-[2-(methoxymethyl)piperidin-1-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]azetidin-3-ol;-   3-ethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperazin-2-one;-   N-[3-methyl-5-(2-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   N-{3-methyl-5-[2-(3-propoxypiperidin-1-yl)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]azetidine-2-carboxylic    acid;-   N-{3-[2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine;-   (2    S)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidine-2-carboxylic    acid;-   2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-1-ol;-   2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-1-ol;-   2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butan-1-ol;-   1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-2-ol;-   3-hydroxy-4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butanoic    acid;-   2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}ethanol;-   N-[3-methyl-5-(2-{[(1-methyl-1H-imidazol-4-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   N,N-dimethyl-N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycinamide;-   N-(3-methyl-5-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyrimidin-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   N-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   1,3-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperazin-2-one;-   N-{3-methyl-5-[2-(4-propyl-1,4-diazepan-1-yl)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine;-   N-methyl-N-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta-alaninamide;-   N-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]prolinamide;-   N-(3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propyl)acetamide;-   5-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}piperidin-2-one;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]prolinamide;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidin-3-ol;-   1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopentanecarboxylic    acid;-   3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}pyrrolidin-2-one;-   3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}pyrrolidin-2-one;-   1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidine-4-carboxylic    acid;-   2-cyano-N-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]acetamide;-   3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoic    acid;-   N-(3-methyl-5-pyrazin-2-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   ethyl    3-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;-   3-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoic    acid;-   ethyl    3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;-   3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoic    acid;-   ethyl    3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;-   3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoic    acid;-   ethyl    3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoate;-   3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoic    acid;-   ethyl    3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;-   3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoic    acid;-   ethyl    3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;-   3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoic    acid;-   ethyl    3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;-   3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoic    acid;-   ethyl    3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;-   3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoic    acid;-   ethyl    3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoate;-   3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoic    acid;-   ethyl 3-(6-{3    [(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;-   3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoic    acid;-   N-(3-methyl-5-pyrimidin-2-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine    ethyl    3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoate;-   3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoic    acid;-   ethyl    3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyridazin-3-yl)propanoate;-   ethyl    3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoate;-   N-(3-methyl-5-pyridazin-3-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine-   N-[3-methyl-5-(6-morpholin-4-ylpyridazin-3-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;-   1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]piperidin-4-ol;-   1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]piperidine-4-carboxamide;-   3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]benzoic    acid;-   4-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]benzoic    acid;-   2-methyl-2-{[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]oxy}propanoic    acid;-   1-[2-(dimethylamino)ethyl]-3,3-dimethyl-1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]urea;-   2-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propan-2-ol;-   1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]piperidine-4-carboxylic    acid-   N-methyl-N-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]glycine;-   3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoic    acid;-   ethyl    3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyridazin-3-yl)propanoate;-   3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyridazin-3-yl)propanoic    acid;-   ethyl    3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyridazin-3-yl)propanoate;-   N-(3-methyl-5-pyridazin-4-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine    ethyl    3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoate;-   3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoic    acid;-   ethyl    3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoate;-   3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoic    acid;-   N-(3-methyl-5-pyrimidin-4-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;-   ethyl    3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoate;-   3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoic    acid;-   ethyl    3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-4-yl)propanoate;-   3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-4-yl)propanoic    acid;-   ethyl    3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoate;-   3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoic    acid;-   3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-2-yl)propanoic    acid;-   ethyl    3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]propanoate;-   3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoic    acid;-   4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic    acid;-   4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic    acid;-   4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic    acid;-   3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-2-yl)propanoic    acid;-   3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]propanoic    acid;-   1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxamide;-   trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylic    acid;-   trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylic    acid; and-   rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylic    acid;    or a pharmaceutically acceptable salt thereof.

In embodiment no. 27, the compound is selected from any one of thecompounds described in Examples 1.1-1.8, 2.1-2.80, 3.1-3.67, 4.1, 5.1,6.1, 6.2, 7.1-7.8 or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of Formula (I) or apharmaceutically acceptable salt thereof in purified form.

Uses of the Compounds

Compounds of Formula (I) or its pharmaceutically acceptable salts andpharmaceutical compositions containing such compounds can be used totreat or prevent a variety of conditions or diseases mediated by Spleentyrosine kinase (Syk). Such conditions and diseases include, but are notlimited to: (1) arthritis, including rheumatoid arthritis, juvenilearthritis, psoriatic arthritis and osteoarthritis; (2) asthma and otherobstructive airways diseases, including chronic asthma, late asthma,severe asthma, asthma exacerbations, airway hyper-responsiveness,bronchitis, bronchial asthma, allergic asthma, intrinsic asthma,extrinsic asthma, dust asthma, adult respiratory distress syndrome,recurrent airway obstruction, and chronic obstruction pulmonary diseaseincluding emphysema; (3) autoimmune diseases or disorders, includingthose designated as single organ or single cell-type autoimmunedisorders, for example Hashimoto's thyroiditis, autoimmune hemolyticanemia, autoimmune atrophic gastritis of pernicious anemia, autoimmuneencephalomyelitis, autoimmune orchitis, Goodpasture's disease,autoimmune thrombocytopenia including idiopathic thrombopenic purpura,sympathetic ophthalmia, myasthenia gravis, Graves' disease, primarybiliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy, those designated as involving systemicautoimmune disorder, for example systemic lupus erythematosis, immunethrombocytopenic purpura, rheumatoid arthritis, Sjogren's syndrome,Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, andadditional autoimmune diseases, which can be B-cell (humoral) based orT-cell based, including Cogan's syndrome, ankylosing spondylitis,Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onsetdiabetes, and thyroiditis; (4) cancers or tumors, includingalimentary/gastrointestinal tract cancer, colon cancer, liver cancer,skin cancer including mast cell tumor and squamous cell carcinoma,breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma andleukemia (including but not limited to acute myelogenous leukemia,chronic myelogenous leukemia, mantle cell lymphoma, NHL B cell lymphomas(e.g., precursor B-ALL, marginal zone B cell lymphoma, chroniclymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma,mediastinal large B-cell lymphoma), Hodgkin lymphoma, NK and T celllymphomas; TEL-Syk and ITK-Syk fusion driven tumors) myelomas includingmultiple myeloma, myeloproliferative disorders kidney cancer, lungcancer, muscle cancer, bone cancer, bladder cancer, brain cancer,melanoma including oral and metastatic melanoma, Kaposi's sarcoma,proliferative diabetic retinopathy, and angiogenic-associated disordersincluding solid tumors, and pancreatic cancer; (5) diabetes, includingType I diabetes and complications from diabetes; (6) eye diseases,disorders or conditions including autoimmune diseases of the eye,keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitisassociated with Behcet's disease and lens-induced uveitis, keratitis,herpetic keratitis, conical keratitis, corneal epithelial dystrophy,keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave'sophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitissicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrineophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, andocular neovascularization; (7) intestinal inflammations, allergies orconditions including Crohn's disease and/or ulcerative colitis,inflammatory bowel disease, coeliac diseases, proctitis, eosinophilicgastroenteritis, and mastocytosis; (8) neurodegenerative diseasesincluding motor neuron disease, Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, Huntington's disease, cerebralischemia, or neurodegenerative disease caused by traumatic injury,strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injuryin stroke, myocardial ischemica, renal ischemia, heart attacks, cardiachypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia; (9)platelet aggregation and diseases associated with or caused by plateletactivation, such as arteriosclerosis, thrombosis, intimal hyperplasiaand restenosis following vascular injury; (10) conditions associatedwith cardiovascular diseases, including restenosis, acute coronarysyndrome, myocardial infarction, unstable angina, refractory angina,occlusive coronary thrombus occurring post-thrombolytic therapy orpost-coronary angioplasty, a thrombotically mediated cerebrovascularsyndrome, embolic stroke, thrombotic stroke, transient ischemic attacks,venous thrombosis, deep venous thrombosis, pulmonary embolus,coagulopathy, disseminated intravascular coagulation, thromboticthrombocytopenic purpura, thromboangiitis obliterans, thrombotic diseaseassociated with heparin-induced thrombocytopenia, thromboticcomplications associated with extracorporeal circulation, thromboticcomplications associated with instrumentation such as cardiac or otherintravascular catheterization, intra-aortic balloon pump, coronary stentor cardiac valve, conditions requiring the fitting of prostheticdevices, and the like; (11) skin diseases, conditions or disordersincluding atopic dermatitis, eczema, psoriasis, scleroderma, pruritusand other pruritic conditions; (12) allergic reactions includinganaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria,angioedema, allergic asthma, or allergic reaction to insect bites, food,drugs, or pollen; (13) transplant rejection, including pancreas islettransplant rejection, bone marrow transplant rejection,graft-versus-host disease, organ and cell transplant rejection such asbone marrow, cartilage, cornea, heart, intervertebral disc, islet,kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin,small intestine, or trachea, and xeno transplantation; (14) low gradescarring including scleroderma, increased fibrosis, cystic fibrosis,keloids, post-surgical scars, pulmonary fibrosis, vascular spasms,migraine, reperfusion injury, and post-myocardial infarction.

The invention thus provides compounds of Formula (I) andpharmaceutically acceptable salts thereof for use in therapy, andparticularly in the treatment of diseases and conditions mediated byinappropriate Syk activity. The inappropriate Syk activity referred toherein is any Syk activity that deviates from the normal Syk activityexpected in a particular patient. Inappropriate Syk activity may takethe form of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of Syk activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase leading to inappropriate oruncontrolled activation.

In a further embodiment, the present invention is directed to methods ofregulating, modulating, or inhibiting Syk for the prevention and/ortreatment of disorders related to unregulated Syk activity.

In a further embodiment, the present invention provides a method oftreatment of a patient suffering from a disorder mediated by Sykactivity, which comprises administering to said patient an effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt, solvate, or a physiologically functional derivative thereof. In afurther embodiment, the present invention provides for the use of acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, or a physiologically functional derivative thereof, inthe preparation of a medicament for the treatment of a disorder mediatedby Syk activity.

In a further embodiment said disorder mediated by Syk activity isasthma. In a further embodiment said disorder is rheumatoid arthritis.In yet another embodiment, said disorder is cancer. In a furtherembodiment said disorder is ocular conjunctivitis.

Yet another aspect of the present invention provides a method fortreating diseases caused by or associated with Fc receptor signalingcascades, including FceRI and/or FcgRI-mediated degranulation as atherapeutic approach towards the treatment or prevention of diseasescharacterized by, caused by and/or associated with the release orsynthesis of chemical mediators of such Fc receptor signaling cascadesor degranulation. In addition, Syk is known to play a critical role inimmunotyrosine-based activation motif (ITAM) signaling, B cell receptorsignaling, T cell receptor signaling and is an essential component ofintegrin beta (1), beta (2), and beta (3) signaling in neutrophils.Thus, compounds of the present invention can be used to regulate Fcreceptor, ITAM, B cell receptor and integrin signaling cascades, as wellas the cellular responses elicited through these signaling cascades.Non-limiting examples of cellular responses that may be regulated orinhibited include respiratory burst, cellular adhesion, cellulardegranulation, cell spreading, cell migration, phagocytosis, calcium ionflux, platelet aggregation and cell maturation.

Compositions and Administration

While it is possible that, for use in therapy, a compound of Formula(I), as well as pharmaceutically acceptable salts thereof, may beadministered as the raw chemical, it is possible to present the activeingredient as a pharmaceutical composition. Accordingly, the inventionfurther provides a pharmaceutical composition, which comprises acompound of Formula (I) and pharmaceutically acceptable salts thereof,and a pharmaceutically acceptable carrier. The compounds of the Formula(I) and pharmaceutically acceptable salts thereof, are as describedabove. The carriers must be acceptable in the sense of being compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof. In accordance with another aspect of the inventionthere is also provided a process for the preparation of a pharmaceuticalcomposition including admixing a compound of the Formula (I), or apharmaceutically acceptable salt thereof, with one or morepharmaceutically acceptable carriers.

Pharmaceutical compositions of the present invention may be presented inunit dose forms containing a predetermined amount of active ingredientper unit dose. Such a unit may contain, for example, 5 μg to 1 g,preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compoundof the Formula (I), depending on the condition being treated, the routeof administration and the age, weight and condition of the patient. Suchunit doses may therefore be administered more than once a day. Preferredunit dosage compositions are those containing a daily dose or sub-dose(for administration more than once a day), as herein above recited, oran appropriate fraction thereof, of an active ingredient. Furthermore,such pharmaceutical compositions may be prepared by any of the methodswell known in the pharmacy art.

Pharmaceutical compositions of the present invention may be adapted foradministration by any appropriate route, for example by the oral(including buccal or sublingual), rectal, topical, inhaled, nasal,ocular, or parenteral (including intravenous and intramuscular) route.Such compositions may be prepared by any method known in the art ofpharmacy, for example by bringing into association the active ingredientwith the carrier(s) or excipient(s). Dosage forms include tablets,troches, dispersions, suspensions, solutions, capsules, creams,ointments, aerosols, and the like.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the oral route, for treating,for example, rheumatoid arthritis.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the nasal route, for treating,for example, allergic rhinitis.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the inhaled route, fortreating, for example, asthma, COPD or ARDS.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the ocular route, fortreating, diseases of the eye, for example, conjunctivitis.

In a further embodiment, the present invention provides a pharmaceuticalcomposition adapted for administration by the parenteral (includingintravenous) route, for treating, for example, cancer.

Pharmaceutical compositions of the present invention which are adaptedfor oral administration may be presented as discrete units such ascapsules or tablets; powders or granules; solutions or suspensions inaqueous or non-aqueous liquids; edible foams or whips; or oil-in-waterliquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release, for example, by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Dosage forms for inhaled administration may conveniently be formulatedas aerosols or dry powders.

For compositions suitable and/or adapted for inhaled administration, itis preferred that the compound or salt of Formula (I) is in aparticle-size-reduced form, and more preferably the size-reduced form isobtained or obtainable by micronisation. The preferable particle size ofthe size-reduced (e.g., micronised) compound or salt or solvate isdefined by a D50 value of about 0.5 to about 10 microns (for example asmeasured using laser diffraction).

Aerosol formulations, e.g., for inhaled administration, can comprise asolution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent. Aerosolformulations can be presented in single or multidose quantities insterile form in a sealed container, which can take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler) which is intended for disposalonce the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferablycontains a suitable propellant under pressure such as compressed air,carbon dioxide or an organic propellant such as a hydrofluorocarbon(HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropaneand 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also takethe form of a pump-atomiser. The pressurised aerosol may contain asolution or a suspension of the active compound. This may require theincorporation of additional excipients e.g., co-solvents and/orsurfactants to improve the dispersion characteristics and homogeneity ofsuspension formulations. Solution formulations may also require theaddition of co-solvents such as ethanol. Other excipient modifiers mayalso be incorporated to improve, for example, the stability and/or tasteand/or fine particle mass characteristics (amount and/or profile) of theformulation.

For pharmaceutical compositions suitable and/or adapted for inhaledadministration, it is preferred that the pharmaceutical composition is adry powder inhalable composition. Such a composition can comprise apowder base such as lactose, glucose, trehalose, mannitol or starch, thecompound of Formula (I) or salt or solvate thereof (preferably inparticle-size-reduced form, e.g., in micronised form), and optionally aperformance modifier such as L-leucine or another amino acid, and/ormetals salts of stearic acid such as magnesium or calcium stearate.Preferably, the dry powder inhalable composition comprises a dry powderblend of lactose and the compound of Formula (I) or salt thereof. Thelactose is preferably lactose hydrate e.g., lactose monohydrate and/oris preferably inhalation-grade and/or fine-grade lactose. Preferably,the particle size of the lactose is defined by 90% or more (by weight orby volume) of the lactose particles being less than 1000 microns(micrometers) (e.g., 10-1000 microns e.g., 30-1000 microns) in diameter,and/or 50% or more of the lactose particles being less than 500 microns(e.g., 10-500 microns) in diameter. More preferably, the particle sizeof the lactose is defined by 90% or more of the lactose particles beingless than 300 microns (e.g., 10-300 microns e.g., 50-300 microns) indiameter, and/or 50% or more of the lactose particles being less than100 microns in diameter. Optionally, the particle size of the lactose isdefined by 90% or more of the lactose particles being less than 100-200microns in diameter, and/or 50% or more of the lactose particles beingless than 40-70 microns in diameter. It is preferable that about 3 toabout 30% (e.g., about 10%) (by weight or by volume) of the particlesare less than 50 microns or less than 20 microns in diameter. Forexample, without limitation, a suitable inhalation-grade lactose isE9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017J D Zwolle, Netherlands).

Optionally, in particular for dry powder inhalable compositions, apharmaceutical composition for inhaled administration can beincorporated into a plurality of sealed dose containers (e.g.,containing the dry powder composition) mounted longitudinally in a stripor ribbon inside a suitable inhalation device. The container isrupturable or peel-openable on demand and the dose of e.g., the drypowder composition can be administered by inhalation via the device suchas the DISKUS® device (GlaxoSmithKline). Other dry powder inhalers arewell known to those of ordinary skill in the art, and many such devicesare commercially available, with representative devices includingAerolizer® (Novartis), Airmax™ (IVAX), ClickHaler® (Innovata Biomed),Diskhaler® (GlaxoSmithKline), Accuhaler (GlaxoSmithKline), Easyhaler®(Orion Pharma), Eclipse™ (Aventis), FlowCaps® (Hovione), Handihaler®(Boehringer Ingelheim), Pulvinal® (Chiesi), Rotahaler®(GlaxoSmithKline), SkyeHaler™ or Certihaler™ (SkyePharma), Twisthaler(Schering Corporation), Turbuhaler® (AstraZeneca), Ultrahaler®(Aventis), and the like.

Dosage forms for ocular administration may be formulated as solutions orsuspensions with excipients suitable for ophthalmic use.

Dosage forms for nasal administration may conveniently be formulated asaerosols, solutions, drops, gels or dry powders.

Pharmaceutical compositions adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

For pharmaceutical compositions suitable and/or adapted for intranasaladministration, the compound of Formula (I) or a pharmaceuticallyacceptable salt or solvate thereof may be formulated as a fluidformulation for delivery from a fluid dispenser. Such fluid dispensersmay have, for example, a dispensing nozzle or dispensing orifice throughwhich a metered dose of the fluid formulation is dispensed upon theapplication of a user-applied force to a pump mechanism of the fluiddispenser. Such fluid dispensers are generally provided with a reservoirof multiple metered doses of the fluid formulation, the doses beingdispensable upon sequential pump actuations. The dispensing nozzle ororifice may be configured for insertion into the nostrils of the userfor spray dispensing of the fluid formulation into the nasal cavity. Afluid dispenser of the aforementioned type is described and illustratedin WO-A-2005/044354, the entire content of which is hereby incorporatedherein by reference. The dispenser has a housing which houses a fluiddischarge device having a compression pump mounted on a container forcontaining a fluid formulation. The housing has at least onefinger-operable side lever which is movable inwardly with respect to thehousing to cam the container upwardly in the housing to cause the pumpto compress and pump a metered dose of the formulation out of a pumpstem through a nasal nozzle of the housing. A particularly preferredfluid dispenser is of the general type illustrated in FIGS. 30-40 ofWO-A-2005/044354.

The following are examples of representative pharmaceutical dosage formsfor the compounds of this invention:

Injectable Suspension (I.M.) mg/mL Compound of Formula (I) 10Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkoniumchloride 1.0 Water for injection to a total volume of 1 mL

Tablet mg/tablet Compound of Formula (I) 25 Microcrystalline Cellulose415 Providone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 500

Capsule mg/capsule Compound of Formula (I) 25 Lactose Powder 573.5Magnesium Stearate 1.5 600

Aerosol Per canister Compound of Formula (I)   24 mg Lecithin, NF LiquidConcentrate  1.2 mg Trichlorofluoromethane, NF 4.025 gmDichlorodifluoromethane, NF 12.15 gm

It will be appreciated that when the compound of the present inventionis administered in combination with other therapeutic agents normallyadministered by the inhaled, intravenous, oral or intranasal route, thatthe resultant pharmaceutical composition may be administered by the sameroutes.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of Formula (I) for the treatment of diseases or conditionsassociated with inappropriate Syk activity, will generally be in therange of 5 μg to 100 mg/kg body weight of recipient (patient) per dayand more usually in the range of 5 μg to 10 mg/kg body weight per day.This amount may be given in a single dose per day or more usually in anumber (such as two, three, four, five or six) of sub-doses per day suchthat the total daily dose is the same. An effective amount of a salt orsolvate, thereof, may be determined as a proportion of the effectiveamount of the compound of Formula (I) per se.

The compositions of the invention can further comprise one or moreadditional therapeutic agents, as discussed in further detail below.Accordingly, in one embodiment, the present invention providescompositions comprising: (i) a compound of Formula (I) or apharmaceutically acceptable salt thereof; (ii) one or more additionaltherapeutic agents, that are not compounds of Formula (I); and (iii) apharmaceutically acceptable carrier, wherein the amounts in thecomposition are together effective to treat one of the disease orconditions discussed above.

Combination Therapy

The compounds of Formula (I) or their pharmaceutically acceptable saltsmay be used in combination, either in a single formulation orco-administered as separate formulations with at least one additionaltherapeutic agent to treat or prevent the diseases and conditionsdescribed herein. For the treatment of the inflammatory diseases,rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD,asthma and allergic rhinititis, these additional therapeutic agentsinclude, but are not limited to: (1) TNF-α inhibitors such as infliximab(Remicade®), etanercept (Enbrel®), adalimumab (Humira®), certolizumabpegol (Cimzia®), and golimumab (Simponi®); (2) non-selective COX-I/COX-2inhibitors (such as piroxicam, diclofenac, propionic acids such asnaproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamatessuch as mefenamic acid, indomethacin, sulindac, etodolac, azapropazone,pyrazolones such as phenylbutazone, salicylates such as aspirin); (3)COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxiband etoricoxib); (4) other agents for treatment of rheumatoid arthritisincluding methotrexate, leflunomide, sulfasalazine, azathioprine,cyclosporin, tacrolimus, penicillamine, bucillamine, actarit,mizoribine, lobenzarit, ciclesonide, hydroxychloroquine,d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold,cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors and CTLA-4-Ig ormimetics thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase(5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonistsuch as zileuton; (6) LTD4 receptor antagonist such as zafirlukast,montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast,cilomilast, AWD-12-281 (Elbion), and PD-168787 (Pfizer); (8)antihistaminic H1 receptor antagonists such as cetirizine,levocetirizine, loratadine, desloratadine, fexofenadine, astemizole,azelastine, levocabastine, olopatidine, methapyrilene andchlorpheniramine; (9) α1- and α2-adrenoceptor agonist vasoconstrictorsympathomimetic agent, such as propylhexedrine, phenylephrine,phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride;(10) anticholinergic agents such as ipratropium bromide, tiotropiumbromide, oxitropium bromide, aclindinium bromide, glycopyrrolate,(R,R)-glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptoragonists such as metaproterenol, isoproterenol, isoprenaline, albuterol,formoterol (particularly the fumarate salt), salmeterol (particularlythe xinafoate salt), terbutaline, orciprenaline, bitolterol mesylate,fenoterol, and pirbuterol, or methylxanthanines including theophyllineand aminophylline, sodium cromoglycate; (12) insulin-like growth factortype I (IGF-1) mimetic; (13) glucocorticosteroids, especially inhaledglucocorticoid with reduced systemic side effects, such as prednisone,prednisolone, flunisolide, triamcinolone acetonide, beclomethasonedipropionate, budesonide, fluticasone propionate, ciclesonide andmometasone furoate; (14) kinase inhibitors such as inhibitors of theJanus Kinases (JAK 1 and/or JAK2 and/or JAK 3 and/or TYK2) such astofacitinib (Pfizer), baricitinib (Incyte), VX-509 (Vertex), ASP-015K(Astellas), GLPG0634 (Galapagos), SB-1578 (SBIO), and AC-430 (AmbitBiosciences); p38 MAPK and IKK2; (15) B-cell targeting biologics such asrituximab (Rituxan®); (16) selective costimulation modulators such asabatacept (Orencia); (17) interleukin inhibitors, such as IL-1 inhibitoranakinra (Kineret) and IL-6 inhibitor tocilizumab (Actemra).

The present invention also provides for so-called “triple combination”therapy, comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof together with beta₂-adrenoreceptor agonist andan anti-inflammatory corticosteroid. Preferably this combination is fortreatment and/or prophylaxis of asthma, COPD or allergic rhinitis. Thebeta₂-adrenoreceptor agonist and/or the anti-inflammatory corticosteroidcan be as described above and/or as described in WO 03/030939 A1.Representative examples of such a “triple” combination are a compound ofFormula (I) or a pharmaceutically acceptable salt thereof in combinationwith the components of Advair® (salmeterol xinafoate and fluticasonepropionate), Symbicort® (budesonide and formoterol fumarate), or Dulera®(mometasone furoate and formoterol fumarate) or a pharmaceuticallyacceptable salt thereof (e.g., salmeterol xinafoate and fluticasonepropionate).

For the treatment of cancer a compound of Formula (I) may be combinedwith an one or more additional therapeutic agents which are anticanceragents. Examples of such agents can be found in Cancer Principles andPractice of Oncology by V. T. Devita and S. Hellman (editors), 6thedition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. Aperson of ordinary skill in the art would be able to discern whichcombinations of agents would be useful based on the particularcharacteristics of the drugs and the cancer involved. Such anticanceragents include, but are not limited to, the following: (1) an estrogenreceptor modulator such as diethylstibestral, tamoxifen, raloxifene,idoxifene, LY353381, LY117081, toremifene, fluoxymestero, and SH646; (2)other hormonal agents including aromatase inhibitors (e.g.,aminoglutethimide, tetrazole anastrozole, letrozole and exemestane),luteinizing hormone release hormone (LHRH) analogues, ketoconazole,goserelin acetate, leuprolide, megestrol acetate and mifepristone; (3)an androgen receptor modulator such as finasteride and other5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole,and abiraterone acetate; (4) a retinoid receptor modulator such asbexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide; (5) an antiproliferativeagent such as antisense RNA and DNA oligonucleotides such as G3139,ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such asenocitabine, carmofur, tegafur, pentostatin, doxifluridine,trimetrexate, fludarabine, capecitabine, galocitabine, cytarabineocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid,emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine,2′-deoxy-2′-methylidenecytidine, 2′-fluoromethylene-2′-deoxycytidine,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine, aminopterin, 5-flurouracil,floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone; (6) a prenyl-proteintransferase inhibitor including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase); (7) an HMG-CoA reductase inhibitor such as lovastatin,simvastatin, pravastatin, atorvastatin, fluvastatin and rosuvastatin;(8) an angiogenesis inhibitor such as inhibitors of the tyrosine kinasereceptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), inhibitors ofepidermal-derived, fibroblast-derived, or platelet derived growthfactors, MMP (matrix metalloprotease) inhibitors, integrin blockers,interferon-α, interleukin-12, erythropoietin (epoietin-α),granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF(sargramostim), pentosan polysulfate, cyclooxygenase inhibitors,steroidal anti-inflammatories, carboxyamidotriazole, combretastatin A-4,squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide,angiostatin, troponin-1, angiotensin II antagonists, heparin,carboxypeptidase U inhibitors, and antibodies to VEGF, endostatin,ukrain, ranpirnase, IM862, acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]-methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate, and3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416); (9) PPAR-γagonists, PPAR-δ agonists, thiazolidinediones (such as DRF2725, CS-011,troglitazone, rosiglitazone, and pioglitazone), fenofibrate,gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555,GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570,PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and(2R)-7-(3-(2-chloro-4-(4-fluorophenoxyl)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697); (9) aninhibitor of inherent multidrug resistance including inhibitors ofp-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922,VX853 and PSC833 (valspodar); (10) an inhibitor of cell proliferationand survival signaling such as inhibitors of EGFR (for example gefitiniband erlotinib), inhibitors of ERB-2 (for example trastuzumab),inhibitors of IGF1R such as MK-0646 (dalotuzumab), inhibitors of CD20(rituximab), inhibitors of cytokine receptors, inhibitors of MET,inhibitors of PI3K family kinase (for example LY294002),serine/threonine kinases (including but not limited to inhibitors of Aktsuch as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138),inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEK(for example CI-1040 and PD-098059) and inhibitors of mTOR (for exampleWyeth CCI-779 and Ariad AP23573); (11) a bisphosphonate such asetidronate, pamidronate, alendronate, risedronate, zoledronate,ibandronate, incadronate or cimadronate, clodronate, EB-1053,minodronate, neridronate, piridronate and tiludronate; (12) γ-secretaseinhibitors, (13) agents that interfere with receptor tyrosine kinases(RTKs) including inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met; (14) anagent that interferes with a cell cycle checkpoint including inhibitorsof ATR, ATM, the Chk1 and Chk2 kinases and cdk and cdc kinase inhibitorsand are specifically exemplified by 7-hydroxystaurosporin, flavopiridol,CYC202 (Cyclacel) and BMS-387032; (15) BTK inhibitors such as PCI32765,AVL-292 and AVL-101; (16) PARP inhibitors including iniparib, olaparib,AG014699, ABT888 and MK4827; (16) ERK inhibitors; (17) mTOR inhibitorssuch as sirolimus, ridaforolimus, temsirolimus, everolimus; and (18)cytotoxic/cytostatic agents.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of histonedeacetylase, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors, proteasomeinhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine,melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine,streptozocin, tasonermin, lonidamine, carboplatin, altretamine,dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosilate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin,mitomycin C, dactinomycin, plicatomycin, bisantrene, mitoxantrone,pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin.

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited tolactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude vincristine, vinblastine, vindesine, vinzolidine, vinorelbine,vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)),paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate,auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, lurtotecan,7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100,BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins include, but are not limitedto inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E,inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosphl andinhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, vorinostat, trichostatin A, oxamflatin, PXD101, MG98,valproic acid and scriptaid.

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1. An example of an “aurora kinase inhibitor” isVX-680.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine, aminopterin, 5-flurouracil,floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG),mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate,cladribine (2-CDA), asparaginase, gemcitabine, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Non-limiting examples of suitable additional therapeutic agents used incancer therapy that may be combined with compounds of Formula (I)include, but are not limited to, abarelix; aldesleukin; alemtuzumab;alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenictrioxide; asparaginase; azacitidine; bendamustine; bevacuzimab;bexarotene; bleomycin; bortezomib; busulfan; calusterone; capecitabine;carboplatin; carmustine; cetuximab; chlorambucil; cisplatin; cladribine;clofarabine; cyclophosphamide; cytarabine; dacarbazine; dactinomycin,actinomycin D; dalteparin; darbepoetin alfa; dasatinib; daunorubicin;degarelix; denileukin diftitox; dexrazoxane; docetaxel; doxorubicin;dromostanolone propionate; eculizumab; Elliott's B Solution;eltrombopag; epirubicin; epoetin alfa; erlotinib; estramustine;etoposide phosphate; etoposide; everolimus; exemestane; filgrastim;floxuridine; fludarabine; fluorouracil; fulvestrant; gefitinib;gemcitabine; gemtuzumab ozogamicin; goserelin acetate; histrelinacetate; hydroxyurea; ibritumomab tiuxetan; idarubicin; ifosfamide;imatinib mesylate; interferon alfa 2a; interferon alfa-2b; irinotecan;ixabepilone; lapatinib; lenalidomide; letrozole; leucovorin; leuprolideacetate; levamisole; lomustine; meclorethamine, nitrogen mustard;megestrol acetate; melphalan, L-PAM; mercaptopurine; mesna;methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone;nandrolone phenpropionate; nelarabine; nilotinib; Nofetumomab;ofatumumab; oprelvekin; oxaliplatin; paclitaxel; palifermin; pamidronat;panitumumab; pazopanib; pegademase; pegaspargase; Pegfilgrastim;pemetrexed disodium; pentostatin; pipobroman; plerixafor; plicamycin,mithramycin); porfimer sodium; pralatrexate; procarbazine; quinacrine;Rasburicase; raloxifene hydrochloride; Rituximab; romidepsin;romiplostim; sargramostim; sargramostim; satraplatin; sorafenib;streptozocin; sunitinib maleate; tamoxifen; temozolomide; temsirolimus;teniposide; testolactone; thioguanine; thiotepa; topotecan; toremifene;tositumomab; trastuzumab; tretinoin; uracil mustard; valrubicin;vinblastine; vincristine; vinorelbine; vorinostat; and zoledronate.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like.

These combinations are of particular interest in respiratory diseasesand are conveniently adapted for inhaled or intranasal delivery.

In one embodiment, the compound of Formula (I) is administered during atime when the additional therapeutic agent(s) exert their prophylacticor therapeutic effect, or vice versa.

In another embodiment, the compound of Formula (I) and the additionaltherapeutic agent(s) are administered in doses commonly employed whensuch agents are used as monotherapy for treating the disorder.

In another embodiment, the compound of Formula (I) and the additionaltherapeutic agent(s) are administered in doses lower than the dosescommonly employed when such agents are used as monotherapy for treatingthe disorder.

In one embodiment, the compound of Formula (I) and the additionaltherapeutic agent(s) are present in the same composition, which issuitable for oral administration.

The compound of Formula (I) and the additional therapeutic agent(s) canact additively or synergistically. A synergistic combination may allowthe use of lower dosages of one or more agents and/or less frequentadministration of one or more agents of a combination therapy. A lowerdosage or less frequent administration of one or more agents may lowertoxicity of the therapy without reducing the efficacy of the therapy.

The doses and dosage regimen of the additional therapeutic agent(s) usedin the combination therapies of the present invention for the treatmentor prevention of a disease or disorder can be determined by theattending clinician, taking into consideration the approved doses anddosage regimen in the package insert; the age, sex and general health ofthe patient; and the type and severity of the disease or conditionmediated by Syk.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of the compound of Formula (I) or a pharmaceuticallyacceptable salt of said compound, optionally at least one additionaltherapeutic agent listed above and a pharmaceutically acceptablecarrier, vehicle or diluent.

Methods of Preparing the Compounds of Formula (I)

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the Formula (I) are prepared in the Examples.

Compounds of general Formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprotecting groups as well as the reaction conditions and order ofreaction steps shall be consistent with the preparation of compounds ofFormula (I). Those skilled in the art will recognize whether astereocenter exists in compounds of Formula (I). Accordingly, thepresent invention includes all possible stereoisomers and includes notonly mixtures of stereoisomers (such as racemic compounds) but theindividual stereoisomers as well. When a compound is desired as a singleenantiomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be effected by any suitable method known in the art. See, forexample, Stereochemistry of Organic Compounds by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The following solvents, reagents, protecting groups, moieties, and otherdesignations may be referred to by their abbreviations in parenthesis:

Me=methyl; Et=ethyl; Pr=propyl; iPr=isopropyl, Bu=butyl;t-Bu=tert-butyl; Ph=phenyl, and Ac=acetyl

μl=microliters

AcOH or HOAc=acetic acid

APCI=atmospheric-pressure chemical ionization

aq=aqueous

Bn=benzyl

Boc or BOC=tert-butoxycarbonyl

Bz=benzoyl

Boc=tert-butoxycarbonyl

Cbz=benyzloxycarbonyl

DCM=dichloromethane:

DMAP=4-Dimethylaminopyridine

DIBAL=diisobutylaluminum hydride

DIEA or Hünig's Base=N,N-diisopropylethylamine

DMA=1,2-dimethylacetamide

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

DTT=dithiothreitol

EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EDTA=ethylenediamine tetraacetic acid

ESI=electrospray ionization

EtOAc=ethyl acetate

g=grams

GST=glutathione S-transferase

h=hour

HMDS=1,1,1,3,3,3-hexamethyldisilazane

HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate

HEX=hexanes

HPLC=high-performance liquid chromatography

HOBt=1-hydroxybenzotriazole

LDA=lithium diisopropylamide

LCMS=liquid chromatography mass spectrometry

min=minute

mg=milligrams

mL=milliliters

mmol=millimoles

Me=methyl

MeOH: methanol

MS=mass spectrometry

NBS=N-bromosuccimide

NMR=nuclear magnetic resonance spectroscopy

rac=racemic mixture

RT or rt=room temperature (ambient, about 25° C.)

sat=saturated

SFC=supercritical fluid chromatography

TBSC1=t-butyldimethylsilyl chloride

TBS=t-butyldimethyl silyl

TEA=triethylamine (Et₃N)

TFA=trifluoroacetic acid

TFAA=trifluoroacetic anhydride

THF=tetrahydrofuran

TLC=thin layer chromatography

TMS=trimethylsilyl

Tris=tris(hydroxymethyl)aminomethane

General Methods

Compounds of the Formula (I) can be prepared according to one of thegeneral synthetic schemes procedures set forth in Schemes 1-4 below,and/or by methods similar to those described in the Examples below.

As shown in Scheme 1 above, compounds of structural subtype (1) areprepared by Suzuki coupling of biaryl halides (2a) with a borylatedreaction partner, C^(y)B(OH)₂. Biaryl halides (2a) are prepared byacid-mediated S_(N)Ar reaction of anilines (3) with halopyrimidines (4).In addition, compounds of structural subtype (1) can be prepared bycoupling boronate esters (2b) with halide C^(y)—X.

Scheme 2 illustrates methods for preparing suitable C^(y) precursors(5), (6), and (8) which bear a carboxylic acid ester. C^(y) precursors(5), (6), and (8) serve as suitable coupling partners for use, forexample, in the methods illustrated above in Scheme 1. As shown inScheme 2, aryl halide (5) is prepared by base-mediated S_(N)Ar reactionof the alcohol alkyl-OC(O)—Y^(s)—OH with dihaloheterocycles (7).Palladium-mediated Negishi coupling of dihaloheterocycles (7) withalkylzinc reagents to yields halo-substituted (6). Additionally,haloheterocycles (6) are borylated using palladium as a catalyst toafford boronic acids (8).

Scheme 3 illustrates methods for preparing compounds of the Formula (I)wherein R^(Cy) is substituted on C^(y) by an amino-substituent. Theamine, HNRR′, is reacted with chloropyrimidines (9) to yieldaminopyrimidine (10) in a base-mediated S_(N)Ar reaction. R and R′ aresubstituents on the amino group such as alkyl groups, or R and R′together with the N atom can form a heterocyclic ring.

Scheme 4 illustrates methods for preparing carboxylic acids (11) andamides (13) from alkyl esters (12). Carboxylic acids (11) are preparedby hydrolysis of alkyl esters (12). The resultant acids (11) alsoprovide amides (13) under commonly used coupling conditions, such asunder carbodiimide-based coupling conditions.

For ease of reference, various intermediates are referred in theExamples below as precursors of various moieties of Compounds of theFormula (I). These moieties are illustrated in the structural formulabelow.

The starting materials and reagents used in preparing compoundsdescribed are either available from commercial suppliers or wereprepared by literature methods known to those skilled in the art.

These examples are being provided to further illustrate the presentinvention. The examples provided below are for illustrative purposesonly; the scope of the invention is not to be considered limited in anyway thereby.

Compounds in the examples which include the indications “(R) or (S)” or“(R or S)” means that the compounds were isolated as a singleenantiomers and the stereochemical configurations of such compounds werenot determined

Where mass spectral (MS) data are presented in the examples below,analysis was performed using an Agilent Technologies 6120 quadrupoleLC/MS. Resolution of enantiomers was typically performed usingsupercritical fluid chromatography utilizing a Chiral Technologiesstationary phase such as OJ-H or OJ column (stationary phase withparticle size of 5 or 10 micron) with a mobile phase of CO₂ and a loweralcohol such as methanol or isopropanol.

EXAMPLES Preparative Example 1 Preparation of Pyrimidin-2-ylaminophenylPrecursors Suitable for Coupling with C^(y) Precursors PreparativeExample 1.1N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine

Step 1: A solution of 3-bromo-5-methylaniline (162.5 g, 873.66 mmol) in1,4-dioxane (2 L) was prepared, and2-chloro-4-(trifluoromethyl)pyrimidine (182 g, 994.54 mmol) andmethanesulfonic acid (97.5 g, 1.02 mol) were added sequentially. Theresulting solution was heated to reflux overnight. The resulting mixturewas cooled and concentrated in vacuo. The residue was diluted with 2 Lof water, then adjusted to pH 7-8 with aqueous saturated sodiumbicarbonate solution, followed by extraction with EtOAc (2×2 L). Theorganic layers were combined, washed with water (2×2 L), dried overanhydrous sodium sulfate and concentrated in vacuo to affordN-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine as alight yellow solid. MS ESI calc'd for C₁₂H₁₀BrF₃N₃ [M+H]⁺ 332, 334.found 332, 334. ¹H NMR (400 MHz, CDCl₃): δ 8.68 (d, J=4.9 Hz, 1H), 7.79(s, 1H), 7.33-7.23 (m, 2H), 7.10-7.06 (m, 2H), 2.36 (s, 3H).

Step 2: To a solution ofN-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (250 g,753.01 mmol) in 1,4-dioxane (3 L) were added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(225 g, 885.83 mmol), KOAc (225 g, 2.30 mol) and Pd(dppf)Cl2 (19 g,25.23 mmol). The resulting solution was heated to reflux overnight. Thesolid was filtered and the filtrate was decolorized by passing through asilica gel column. The fractions were collected and concentrated invacuo. This resulted in a portion of purified product and a portion ofcrude product. The crude product was decolorized again with activecarbon to provide an additional aliquot of product. The two portions ofpurified product were combined to affordN-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amineas a white solid. MS ESI calc'd for C₁₅H₂₂BF₃N₃O₂ [M+H]⁺ 380. found 380.1H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=5.2, 1 H), 7.75 (s, 1H), 7.64 (s,1H), 7.40-7.30 (m, 2H), 7.00 (d, J=5.2, 1 H), 2.39 (s, 3H), 1.35 (s,12H).

Preparative Example 1.2N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine

To a solution of 2-chloro-4-cyclopropyl-pyrimidine (12.5 g, 81 mmol) and3-bromo-5-methylaniline (18.1 g, 97 mmol) in 1,4-dioxane (100 mL) wasadded pivalic acid (9.3 mL, 81 mmol). The resulting mixture was heatedto reflux and left stirring for 10 hours. The mixture was allowed tocool to room temperature and hexanes were added (80 mL). The slurry wasfiltered and the filtrate was washed with MeOH to afford a portion ofN-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine. The motherliquors were concentrated, absorbed on silica gel and purified by silicagel column chromatography (EtOAc/Hex) to afford additionalN-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine as a whitesolid. MS ESI calcd. for C₁₄H₁₅BrN₃ [M+H]⁺ 304 and 306. found 304 and306.

The pyrimidin-2-ylaminophenyl precursor in the table below was preparedusing a similar method as the one described in Preparative Example 1.1

PrepEx [M + H]⁺ No. Structure Name Observed 1.3

4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]pyrimidin-2-amine362

Preparative Example 2 Preparation of C^(y) Precursors Suitable forCoupling with Pyrimidin-2-ylaminophenyl Precursors Preparative Example2.1 Ethyl 4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate

To a solution of 5-bromo-2-chloro pyrimidine (1.00 g, 5.17 mmol) andethyl 4-hydroxycyclohexanoate (0.834 mL, 5.17 mmol) in DMF (20 mL) wasadded sodium hydride NaH (60% weight in mineral oil, 0.227 g, 5.69mmol). The reaction mixture was stirred for 16 hours before beingdiluted with saturated aqueous sodium bicarbonate (50 mL), ethyl acetate(50 mL), and diethyl ether (50 mL). The layers were separated and theorganic layer was washed with water (3×50 mL) and then brine (50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by chromatography on silica gel(ethyl acetate/hexanes) to yield ethyl4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate as a mixture of cisand trans isomers. MS ESI calc'd. for C₁₃H₁₈BrN₂O₃ [M+H]⁺ 329 and 331.found 329 and 331.

Preparative Example 2.2 Ethyl-(6-chloropyrazin-2-yl)propanoate

To a suspension of 2,6-dichloropyrazine (1.90 g, 12.8 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.295 g, 0.255 mmol) in THF(10 mL) was added 3-ethoxy-3-oxypropylzinc bromide solution (0.5 M inTHF, 25.5 mL, 12.75 mmol) over 6 minutes using a syringe. After twohours at room temperature, the reaction mixture was heated to reflux foreighteen hours. After cooling to room temperature, the reaction mixturewas diluted with water (50 mL) and diethyl ether (100 mL). The layerswere separated and the aqueous layer was extracted twice with diethylether (50 mL, 25 mL). The combined organic layers were washed withsaturated aqueous sodium bicarbonate (50 mL) and brine, dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel (ethylacetate/hexanes) to yield ethyl 3-(6-chloropyrazin-2-yl)propanoate. MSESI calc'd. for C₉H₁₂ClN₂O₂ [M+H]⁺ 215. found 215. ¹H NMR (500 MHz,CDCl₃) δ 8.44 (s, 1H), 8.42 (s, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.11 (t,J=7.2 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H).

The C^(y) precursors in the table below were prepared using a similarmethod as the one described in Preparative Example 2.2

PrepEx [M + H]⁺ No. Structure Name Observed 2.3

ethyl 3-(6- chloropyridazin-3- yl)propanoate 215 2.4

ethyl 3-(6- bromopyrimidin-4- yl)propanoate 259, 261 2.5

ethyl 3-(5- bromopyrazin-2- yl)propanoate 259, 261 2.6

ethyl 3-(5- chloropyrimidin-2- yl)propanoate 215

Preparative Example 2.7 [2-(3-Ethoxy-3-oxopropyl)pyrimidin-5-yl]boronicacid

Step 1: 5-Chloro-2-iodopyrimidine (4 g, 16.64 mmol) andtetrakis(triphenylphosphine)palladium(0) (1.92 g, 1.66 mmol) weresuspended in THF (83 mL). 3-Ethoxy-3-oxopropylzinc bromide (33.3 mL,16.64 mmol) was added, and the resultant mixture was stirred at roomtemperature for 18 hours. The mixture was diluted with saturatedammonium chloride and water (1:1) and extracted with EtOAc (3×100 mL).The combined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (EtOAc:Hexanes) to giveethyl 3-(5-chloropyrimidin-2-yl)propanoate. MS ESI calcd forC₉H₁₂ClN₂O₂[M+H]⁺ 215. found 215. ¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (s,2H), 4.00 (q, J=7.1 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz,2H), 1.11 (t, J=7.1 Hz, 3H).

Step 2: 3-(5-Chloropyrimidin-2-yl)propanoate (1.49 g, 6.97 mmol),bis(pinacolato)diboron (1.95 g, 7.67 mmol), and potassium acetate (1.1g, 11.15 mmol) were suspended in dioxane (34.8 mL). The system wasevacuated and then purged with Ar three times before addingbis(tricyclohexylphosphine)palladium(0) (0.12 g, 0.17 mmol). The systemwas evacuated and then purged with Ar three times before capping andheating the mixture to 85° C. for 16 hours. The reaction was allowed tocool to room temperature, filtered through CELITE, and concentrated invacuo. The residue was purified by reverse phase column chromatographyusing a C18 column eluting with 3:97 to 100:0 acetonitrile:water with0.1% ammonium hydroxide to give[2-(3-ethoxy-3-oxopropyl)pyrimidin-5-yl]boronic acid. MS ESI calcd forC₉H₁₄BN₂O₄ [M+H]⁺ 225. found 225. ¹H NMR (500 MHz, DMSO-d₆) δ 8.89 (s,1H), 8.52 (s, 1H), 4.00 (q, J=7.1 Hz, 2H), 3.12 (t, J=7.0 Hz, 2H), 2.78(t, J=7.0 Hz, 2H), 1.11 (t, J=7.1 Hz, 3H).

Preparative Example 2.8 Methyltrans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate,isomer 1 and isomer 2

Step 1: To a mixture of 5-chloro-2-iodopyrimidine (0.2 g, 0.83 mmol) andmethyl trans-4-acetylcyclohexanecarboxylate (0.15 g, 0.83 mmol) in THF(4 mL) was added n-butyllithium (2.5 M in hexanes, 0.33 mL, 0.83 mmol)dropwise under a nitrogen atmosphere at −78° C. The mixture was stirredat −78° C. for 2 hours, and then quenched with saturate aqueous ammoniumchloride solution. The mixture was extracted with ethyl acetate, and thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bypreparative TLC to afford methyltrans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate.MS ESI calc'd for C₁₄H₂₀ClN₂O₃ [M+H]⁺ 299. found 299. ¹H NMR: (400 MHz,CDCl₃) δ 8.67 (s, 2H), 3.63 (s, 3H), 2.22-2.16 (m, 1H), 2.07-1.97 (m,2H), 1.86-1.83 (m, 2H), 1.52 (s, 3H), 1.46-1.19 (m, 6H).

Step 2: Methyltrans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylatewas separated into its two enantiomers by SFC: column, Chiralpak AD-H250*4.6 mm I.D., Sum; mobile phase, ethanol (0.05% diethylamine) in CO₂from 5% to 40%; flow rate, 2.35 mL/minute; wavelength, 220 nm. Isomer1—faster eluting; Isomer 2, slower eluting.

Preparative Example 3 Coupling of C^(y) Precursors withPyrimidin-2-ylaminophenyl Precursors Preparative Example 3.1 Ethyl4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylate

A suspension ofN-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine(150 mg, 0.396 mmol), ethyl4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylate (130 mg, 0.396mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.026 g, 0.032 mmol), 1,4-dioxane (3.6 mL),water (0.36 mL), and aqueous sodium carbonate (2 M, 0.396 mL, 0.791mmol) was placed under an argon atmosphere by performing 6 vacuum/argoncycles. The reaction mixture was then heated to 160° C. for 10 minutesusing a microwave reactor. The resulting suspension was diluted withethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution(15 mL). The layers were separated, and the organic layer was washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by chromatography on silicagel (ethyl acetate/hexanes) to afford ethyl4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylateas a mixture of cis and trans isomers. MS ESI calc'd. for C₂₅H₂₇F₃N₅O₃[M+H]⁺ 502. found 502.

Example 1 Preparation of Compounds of Formula (I) Using the GeneralMethods Illustrated in Scheme 1 Example 1.1N-(3-methyl-5-pyrimidin-5-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine

N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (70 mg,0.211 mmol), pyrimidin-5-ylboronic acid (52 mg, 0.422 mmol),PdCl₂(dppf)-dichloromethane adduct (34.4 mg, 0.042 mmol), and aqueoussodium carbonate (2 M, 211 μL, 0.422 mmol), were suspended in2-methyltetrahydrofuran (1.05 mL). The vessel was heated to 60° C. for14 hours. Si-Dimercaptotriazine (222 mg, 0.126 mmol) and acetonitrile (3mL) were added to the mixture and allowed to stir for 4 hours at roomtemperature. The reaction mixture was filtered (washing with 1.5 mLDMSO) and concentrated under reduced pressure at 40° C. The mixture wasfiltered and was purified by mass triggered reverse phase HPLC (57-91%acetonitrile in water+0.1% formic acid) to affordN-(3-methyl-5-pyrimidin-5-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amineas a formate salt. MS ESI calcd for C₁₆H₁₃F₃N₅ [M+H]⁺ 332. found 332. ¹HNMR (600 MHz, DMSO-d₆) δ 10.28 (s, 1H), 9.16 (s, 1H), 9.03 (s, 2H), 8.81(d, J=5.2 Hz, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.26 (d, J=5.5 Hz, 2H).

The following examples in Table A were prepared in a manner analogous tothat described in general Scheme 1.

TABLE A

[M + H]⁺ [M + H]⁺ Ex. R^(cy) R¹ Name Calc′d Obsv′d Form(s) 1.2 —OCH₃—CF₃ N-[3-(2-methoxypyrimidin-5- 362 362 Formate yl)-5-methylphenyl]-4-Salt (trifluoromethyl)pyrimidin-2- amine 1.3 —NH₂ —CF₃N-[3-(2-aminopyrimidin-5- 347 347 Formate yl)-5-methylphenyl]-4- Salt(trifluoromethyl)pyrimidin-2- amine 1.4 —N(H)(CH₂)₂—OCH₃ —CF₃N-(3-{2-[(2- 405 405 Formate methoxyethyl)amino]pyrimidin- Salt5-yl}-5-methylphenyl)-4- (trifluoromethyl)pyrimidin-2- amine 1.5—CH₂CH₂CO₂H —OCH₃ 3-(5-{3-[(4- 366 366 Ammonium methoxypyrimidin-2- Saltyl)amino]-5- methylphenyl}pyrimidin-2- yl)propanoic acid 1.6—CH₂CH₂CO₂CH₂CH₃

ethyl 3-(5-{3-[(4- cyclopropylpyrimidin-2- yl)amino]-5-methylphenyl}pyrimidin-2- yl)pronanoate 404 404 Formate Salt 1.7—CH₂CH₂CO₂CH₂CH₃ —CH₃ ethyl 3-(5-{3-methyl-5-[(4- 378 378 Formatemethylpyrimidin-2- Salt yl)amino]phenyl}pyrimidin- 2-yl)propanoate 1.8—CH₂CH₂CO₂CH₂CH₃ —OCH₃ ethyl 3-(5-{3-[(4- 394 394 Formatemethoxypyrimidin-2- Salt yl)amino]-5- methylphenyl}pyrimidin-2-yl)propanoate

Example 2 Preparation of Compounds of Formula (I) Using the GeneralMethods Illustrated in Scheme 3 Example 2.12-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,3-diol

Step 1: Sodium carbonate (aq) (12 mL, 23.7 mmol) was added to a mixtureofN-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine(4.5 g, 11.9 mmol), bromopyrimidine (2.33 g, 12.0 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (0.491 g, 0.601 mmol), and 2-Me-THF (40 mL).The mixture was placed under an argon atmosphere by performing 2vacuum/argon cycles and heat to 86° C., overnight. Upon cooling to roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were washed withsaturated aqueous NaHCO₃ solution and brine, dried over sodium sulfate,filtered and concentrated in reduced pressure. The crude reactionmixture was purified by triturating with ethyl acetate (˜8 mL), DCM (˜3mL), and MeOH (1 mL), and the product was collected by filtration. Theproduct was washed with ethyl acetate and DCM and further dried underreduced pressure to affordN-[3-(2-chloropyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amineMS ESI calcd for C₁₆H₁₂ClF₃N₅ [M+H]⁺ 366. found 366.

Step 2: 2-Amino-2-methyl-1,3-propanediol (28.7 mg, 0.273 mmol),potassium phosphate, tribasic (58 mg, 0.273 mmol), andN-[3-(2-chloropyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine(50 mg, 0.137 mmol) were dissolved in DMSO (300 μL). The mixture washeated to 130° C. for 48 hours, and then allowed to cool to roomtemperature. The mixture was diluted with DMSO (0.7 mL), filtered, andpurified by reverse phase preparative HPLC (0:100 to 95:5acetonitrile:water+0.1% formic acid) to afford2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,3-diol.MS ESI calcd for C₂₀H₂₂F₃N₆O₂ [M+H]⁺ 332. found 332. ¹H NMR (600 MHz,DMSO-d₆) δ 10.17 (s, 1H), 8.80 (d, J=5.2 Hz, 1H), 8.52 (d, J=23.4 Hz,2H), 7.82 (s, 1H), 7.43 (s, 1H), 7.23 (d, J=5.1 Hz, 1H), 7.08 (s, 1H),6.36 (s, 1H), 3.60-3.50 (m, 4H), 2.30 (s, 3H), 1.25 (d, J=12.1 Hz, 3H).

The following compounds in Table B were also prepared using the generalmethods described in Scheme 3, and in a manner analogous to thatdescribed in Example 2.1.

TABLE B

[M + H]⁺ [M + H]⁺ Ex. R^(cy) Name Calc′d Obsv′d Form(s) 2.2 

2-methyl-N-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]alanine 433 433 Free Base 2.3 

1-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}cyclopropanecarboxylic acid 431431 Free Base 2.4 

l-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}cyclobutanecarboxylic acid 445 445Free Base 2.5 

1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-L- proline 445 445 Free Base 2.6 

(2S)-l-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]azetidine-2-carboxylic acid 431 431 FreeBase 2.7 

3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}pyrrolidin-2-one 430 430 TFA Salt,Formate Salt 2.8  —N(H)(CH₂)₂CO₂H N-[5-(3-methyl-5-{[4- 419 419 Formate(trifluoromethyl)pyrimidin-2- Salt yl]amino}phenyl)pyrimidin-2-yl]-beta-alanine 2.9 

N-methyl-N-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-L- alanine 433 433 Formate Salt 2.10

l-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]pyrrolidin-3-ol 417 417 Formate Salt2.11 —N(H)(CH₂)₃CO₂H 4-{[5-(3-methyl-5-{[4- 433 433 Formate(trifluoromethyl)pyrimidin-2- Salt yl]amino}phenyl)pyrimidin-2-yl]amino}butanoic acid 2.12 —N(H)CH₂CO₂H N-[5-(3-methyl-5-{[4- 405 405Formate (trifluoromethyl)pyrimidin-2- Salt yl]amino}phenyl)pyrimidin-2-yl]glycine 2.13

3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propane-1,2-diol 421 421 FormateSalt 2.14

N-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-L- norvaline 447 447 Formate Salt 2.15

1,1-difluoro-3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propan-2-ol 441 441 Formate Salt2.16

N-(3-{2-[(1,1- dioxidotetrahydrothiophen-3- yl)amino]pyrimidin-5-yl}-5-methylphenyl)-4- (trifluoromethyl)pyrimidin-2- 465 465 Formate Salt 2.17

N-[3-methyl-5-(2-{[(1-methyl-1H- pyrazol-4-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4- (trifluoromethyl)pyrimidin-2-amine 441 441 Formate Salt2.18

N-{3-methyl-5-[2-(tetrahydrofuran-3- ylamino)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine 417 417 Formate Salt 2.19

N-(3-{2-[(1,4-dioxan-2- ylmethyl)amino]pyrimidin-5-yl}-5-methylphenyl)-4- (trifluoromethyl)pyrimidin-2-amine 447 447 Formate Salt2.20

N-{3-[2-(1,1-dioxidothiomorpholin-4-yl)pyrimidin-5-yl]-5-methylphenyl}-4- (trifluoromethyl)pyrimidin-2-amine465 465 Formate Salt 2.21

N-(3-methyl-5-{2-[(1-pyridin-2- ylethyl)amino]pyrimidin-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine 452 452 Formate Salt 2.22

5-({[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}methyl)pyrrolidin-2-one 444 444Formate Salt 2.23

2-{4-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]morpholin-2-yl}ethanol 461 461 FormateSalt 2.24

4-methyl-1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-1,4- diazepan-5-one 458 458 Formate Salt2.25

N-(3-{2-[2-(methoxymethyl)morpholin-4-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine 461 461 Formate Salt 2.26

2-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}ethanesulfonamide 454 454 FormateSalt 2.27

3-methyl-1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperidin-3-ol 445 445 Formate Salt 2.28

3-methyl-1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]pyrrolidin-3-ol 431 431 Formate Salt2.29

4-methyl-1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperidin-4-ol 445 445 Formate Salt 2.30

2-{methyl[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}ethanol 405 405 Formate Salt 2.31

2,2′-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]imino}diethanol 435 435 Formate Salt2.32

N-methyl-N-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]glycine 419 419 Formate Salt 2.33

N-[3-(2-{[2-(1H-imidazol-4- yl)ethyl]amino}pyrimidin-5-yl)-5-methylphenyl]-4- (trifluoromethyl)pyrimidin-2-amine 441 441 Formate Salt2.34

3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propan-1-ol 405 405 Formate Salt2.35

4-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}butan-1-ol 419 419 Formate Salt2.36

(1-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}cyclopentyl)methanol 445 445Formate Salt 2.37

N~2~-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]glycinamide 404 404 Formate Salt 2.38

O-methyl-N-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]serine 449 449 Formate Salt 2.39

N~3~-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta- alaninamide 418 418 Formate Salt2.40

N-{3-[2-(4-acetylpiperazin-1- yl)pyrimidin-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine 458 458 Formate Salt 2.41

N-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]serine 435 435 Formate Salt 2.42

3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}azepan-2-one 458 458 Formate Salt2.43

3-{methyl[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propane-1,2-diol 435 435 FormateSalt 2.44

N-methyl-N~2~-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]glycinamide 418 418 Formate Salt 2.45

N-[2-(1,3-dioxolan-2-yl)ethyl]-N- methyl-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2- yl]amino}phenyl)pyrimidin-2-amine 461 461Formate Salt 2.46

4-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperazin-2-one 430 430 Formate Salt2.47

2-methyl-1-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propan-2-ol 419 419 Formate Salt2.48

N-[3-methyl-5-(2-{[2- (methylsulfonyl)ethyl]amino}pyrimidin-5-yl)phenyl]-4- (trifluoromethyl)pyrimidin-2-amine 453 453 Formate Salt2.49

N-(3-{2-[2-(methoxymethyl)piperidin-1-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine 459 459 Formate Salt 2.50

1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]azetidin-3-ol 403 403 Formate Salt 2.51

3-ethyl-4-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperazin-2-one 458 458 Formate Salt2.52

N-[3-methyl-5-(2-{[(1-methyl-1H- imidazol-5-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4- (trifluoromethyl)pyrimidin-2-amine 441 441 Formate Salt2.53

N-{3-methyl-5-[2-(3-propoxypiperidin- 1-yl)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine 473 473 Formate Salt 2.54

1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]azetidine-2-carboxylic acid 431 431Formate Salt 2.55

N-{3-[2-(4-ethylpiperazin-1- yl)pyrimidin-5-yl]-5-methylphenyl}-4-{trifluoromethyl)pyrimidin-2-amine 444 444 Formate Salt 2.56

(2S)-1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperidine-2-carboxylic acid 459 459Formate Salt 2.57

2-methyl-2-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propan-1-ol 419 419 Formate Salt2.58

2-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propan-1-ol 405 405 Formate Salt2.59

2-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}butan-1-ol 419 419 Formate Salt2.60

1-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propan-2-ol 405 405 Formate Salt2.61

3-hydroxy-4-{[5-(3-methyl-5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}butanoic acid 449 449 Formate Salt2.62

2-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}ethanol 391 391 Formate Salt 2.63

N-[3-methyl-5-(2-{[(1-methyl-1H- imidazol-4-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4- (trifluoromethyl)pyrimidin-2-amine 441 441 Formate Salt2.64

N,N-dimethyl-N~2~-[5-(3-methyl-5- {[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]glycinamide 432 432 Formate Salt 2.65

N-(3-methyl-5-{2-[4-(2,2,2- trifluoroethyl)piperazin-1-yl]pyrimidin-5-yl}phenyl)-4- (trifluoromethyl)pyrimidin-2-amine 498 498 Formate Salt2.66

N-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine 445 445 Formate Salt 2.67

1,3-dimethyl-4-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperazin-2-one 458 458 Formate Salt2.68

N-{3-methyl-5-[2-(4-propyl-1,4- diazepan-1-yl)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine 472 472 Formate Salt 2.69

N-methyl-N~3~-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta- alaninamide 432 432 Formate Salt2.70

N-methyl-1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]prolinamide 458 458 Formate Salt 2.71

N-(3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}propyl)acetamide 446 446 FormateSalt 2.72

(5R)-5-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}piperidin-2-one 444 444 FormateSalt 2.73

(5S)-5-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}piperidin-2-one 444 444 FormateSalt 2.74

1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]prolinamide 444 444 Formate Salt 2.75

1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperidin-3-ol 431 431 Formate Salt 2.76

1-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}cyclopentanecarboxylic acid 459459 Free Base 2.77

3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}pyrrolidin-2-one 430 430 Free Base2.78

3-{[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]amino}pyrrolidin-2-one 430 430 Free Base2.79

1-[5-(3-methyl-5-{[4- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]piperidine-4-carboxylic acid 459 459Free Base 2.80

2-cyano-N-methyl-N-[5-(3-methyl-5- {[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2- yl]acetamide 428 428 TFA Salt

Example 3 Additional Compounds of Formula (I) Using the General MethodsIllustrated in Scheme 1 Example 3.13-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoicacid

Step 1: PdCl₂(dppf)-CH₂Cl₂ adduct (0.012 g, 0.015 mmol),N-(3-bromo-5-methylphenyl)-4-cyclopropylpyrimidin-2-amine (0.036 g,0.120 mmol), [2-(3-ethoxy-3-oxopropyl)pyrimidin-5-yl]boronic acid (0.022g, 0.1 mmol), and sodium carbonate (100 μL, 0.200 mmol) were suspendedin dioxane (750 uL) and heated to 100° C. for 14 hours.Si-dimercaptotriazine (0.185 g, 0.1 mmol) was added to the reactionmixture. The vessel was sealed and allowed to stir at room temperaturefor 4 hours. The mixture was filtered, washing with DMSO (1 mL) andconcentrated under reduced pressure at 40° C. The residue, dissolved in2 mL of DMSO, was purified by mass triggered reverse phase HPLC toafford ethyl3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoate.MS ESI calcd. For C₂₃H₂₆N₅O₂ [M+H]⁺ 404. found 404. ¹H NMR (600 MHz,DMSO-d₆) δ 9.46 (s, 1H), 8.92 (s, 2H), 8.24 (d, J=5.0 Hz, 1H), 7.96 (s,1H), 7.55 (s, 1H), 7.10 (s, 1H), 6.78 (d, J=5.1 Hz, 1H), 4.01 (q, J=7.1Hz, 2H), 3.18 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.0 Hz, 2H), 2.31 (s, 3H),1.99 (m, 1H), 1.12 (t, J=7.1 Hz, 3H), 1.06-0.96 (m, 4H).

Step 2: Sodium hydroxide (0.500 mL, 0.500 mmol) and methanol (0.5 mL)were added to a vessel containing ethyl3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-2-yl)propanoate(40 mg, 0.11 mmol). The vessel was heated in a microwave reactor to 110°C. for 10 minutes. The contents of the vial were filtered, washing withDMSO (1 mL), and the reaction mixture was concentrated under reducedpressure at 40° C. via Genevac. The residue, dissolved in 2 mL of DMSO,was purified by mass triggered reverse phase HPLC to give3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoicacid. MS ESI calcd. for C₂₁H₂₂N₅O₂ [M+H]⁺ 376. found 376. ¹H NMR (600MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.92 (m, 2H), 8.24 (d, J=5.0 Hz, 1H), 7.95(s, 1H), 7.56 (s, 1H), 7.10 (s, 1H), 6.78 (d, J=5.1 Hz, 1H), 3.13 (t,J=7.0 Hz, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.31 (s, 3H), 1.98 (d, J=4.8 Hz,1H), 1.02 (m, 4H).

The examples in Tables C-I were prepared according to the methodsdescribed for Example 3.1. In some cases, step 2 was omitted.

TABLE C

[M + H]+ [M + H]+ Ex. R^(cy) R¹ R⁴ Name Calc′d Obsv′d Form(s) 3.2 

—CF₃ —CH₃ N-(3-methyl-5- pyrazin-2-ylphenyl)-4- (trifluoromethyl) 332332 Free Base, Formate pyrimidin-2-amine Salt 3.3 

—CF₃ —H ethyl 3-[5-(3-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrazin-2- yl]propanoate 418 418 Formate Salt 3.4 

—CF₃ —H 3-[5-(3-{[4- (trifluoromethyl) pyrimidin-2- yl]amino}phenyl)pyrazin-2-yl] propanoic acid 390 390 Formate Salt 3.5 

—OCH₃ —CH₃ ethyl 3-(5-{3-[(4- methoxypyrimidin- 2-yl)amino]-5-methylphenyl}pyrazin- 2-yl)propanoate 394 394 Formate Salt 3.6 

—OCH₃ —CH₃ 3-(5-{3-[(4- methoxypyrimidin- 2-yl)amino]-5-methylphenyl}pyrazin- 2-yl)propanoic acid 366 366 Formate Salt 3.7 

—CF₃ —CH₃ ethyl 3-[5-(3- methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrazin-2- yl]propanoate 432 432 Formate Salt 3.8 

—CF₃ —CH₃ 3-[5-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrazin-2-yl] propanoic acid 404 404 Formate Salt 3.9 

—CH₃ —CH₃ ethyl 3-(5-{3- methyl-5-[(4- methylpyrimidin-2-yl)amino]phenyl} pyrazin-2- yl)propanoate 378 378 Formate Salt 3.10

—CH₃ —CH₃ 3-(5-{3-methyl-5-[(4- methylpyrimidin-2- yl)amino]phenyl}pyrazin-2-yl)propanoic acid 350 350 Formate Salt 3.11

—CH₃ ethyl 3-(5-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5-methylphenyl}pyrazin- 2-yl)propanoate 404 404 Formate Salt 3.12

—CH₃ 3-(5-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5-methylphenyl}pyrazin- 2-yl)propanoic acid 376 376 Formate Salt

TABLE D

[M + H]⁺ [M + H]⁺ Ex. R^(cy) R¹ R⁴ Name Calc′d Obsv′d Form(s) 3.13

—CF₃ —H ethyl 3-[6-(3-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrazin-2- 418 418 Formate Salt yl]propanoate 3.14

—CF₃ —H 3-[6-(3-{[4- (trifluoromethyl) pyrimidin-2- yl]amino}phenyl)pyrazin-2- 390 390 Formate Salt yl]propanoic acid 3.15

—OCH₃ —CH₃ ethyl 3-(6-{3-[(4- methoxypyrimidin- 2-yl)amino]-5-methylphenyl} pyrazin-2- 394 394 Formate Salt yl)propanoate 3.16

—OCH₃ —CH₃ 3-(6-{3-[(4- methoxypyrimidin- 2-yl)amino]-5- methylphenyl}pyrazin-2- 366 366 Ammonium Salt yl)propanoic acid 3.17

—CF₃ —CH₃ ethyl 3-[6-(3- methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) 432 432 Formate Salt pyrazin-2- yl]propanoate 3.18

—CF₃ —CH₃ 3-[6-(3-methyl-5- {[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) 404 404 Formate Salt pyrazin-2- yl]propanoic acid 3.19

—CH₃ —CH₃ ethyl 3-(6-{3- methyl-5-[(4- methylpyrimidin-2-yl)amino]phenyl} pyrazin-2- 378 378 Formate Salt yl)propanoate 3.20

—CH₃ —CH₃ 3-(6-{3-methyl-5- [(4- methylpyrimidin-2- yl)amino]phenyl}pyrazin-2- 350 350 Formate Salt yl)propanoic acid 3.21

—CH₃ ethyl 3-(6-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5-methylphenyl} pyrazin-2- 404 404 Formate Salt yl)propanoate 3.22

—CH₃ 3-(6-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5- methylphenyl}pyrazin-2- 376 376 Formate Salt yl)propanoic acid

TABLE E

[M + H]+ [M + H]+ Ex. R^(cy) R¹ R⁴ Name Calc′d Obsv′d Form(s) 3.23

—CF₃ —CH₃ N-(3-methyl-5- pyrimidin-2- ylphenyl)-4- 332 332 Formate Salt(trifluoromethyl) pyrimidin-2-amine

TABLE F

[M + H]⁺ [M + H]⁺ Ex. R^(cy) R¹ R⁴ Name Calc′d Obsv′d Form(s) 3.24

—CF₃ —H ethyl 3-[6-(3-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3- yl]propanoate 418 418 Formate Salt 3.25

—CF₃ —H 3-[6-(3-{[4- (trifluoromethyl) pyrimidin-2- yl]amino}phenyl)pyridazin-3-yl] propanoic acid 390 390 Formate Salt 3.26

—OCH₃ —CH₃ ethyl 3-(6-{3-[(4- methoxypyrimidin-2- yl)amino]-5-methylphenyl} pyridazin-3- yl)propanoate 394 394 Formate Salt 3.27

—CF₃ —CH₃ ethyl 3-[6-(3-methyl- 5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3- yl]propanoate 432 432 Free Base 3.28

—CF₃ —CH₃ N-(3-methyl-5- pyridazin-3- 332 332 Formate Salt ylphenyl)-4-(trifluoromethyl) pyrimidin-2-amine 3.29

—CF₃ —CH₃ N-[3-methyl-5-(6- morpholin-4- ylpyridazin-3- yl)phenyl]-4-(trifluoromethyl) pyrimidin-2-amine 417 417 TFA Salt 3.30

—CF₃ —CH₃ 1-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3-yl] piperidin-4-ol 431 431 TFA Salt 3.31

—CF₃ —CH₃ 1-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3- yl]piperidine- 4-carboxamide 458 458 TFASalt 3.32

—CF₃ —CH₃ 3-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3- yl]benzoic acid 452 452 TFA Salt 3.33

—CF₃ —CH₃ 4-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3- yl]benzoic acid 452 452 TFA Salt 3.34

—CF₃ —CH₃ 2-methyl-2-{[6-(3- methyl-5-{[4- (trifluoromethyl)pyrimidin-2- yl]amino}phenyl) 434 434 TFA Salt pyridazin-3-yl]oxy}propanoic acid 3.35

—CF₃ —CH₃ 1-[2- (dimethylamino) ethyl]-3,3-dimethyl-1-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2- 489 489 TFA Saltyl]amino}phenyl) pyridazin-3-yl]urea 3.36

—CF₃ —CH₃ 2-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) 390 390 TFA Salt pyridazin-3-yl] propan-2-ol 3.37

—CF₃ —CH₃ 1-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3- yl]piperidine- 4-carboxylic acid 459 459TFA Salt 3.38

—CF₃ —CH₃ N-methyl-N-[6-(3- methyl-5-{[4- (trifluoromethyl) pyrimidin-2-419 419 TFA Salt yl]amino}phenyl) pyridazin-3-yl]glycine 3.39

—CF₃ —CH₃ 3-[6-(3-methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyridazin-3-yl] propanoic acid 404 404 Formate Salt3.40

—CH₃ —CH₃ ethyl 3-(6-{3-methyl- 5-[(4- methylpyrimidin-2-yl)amino]phenyl} pyridazin-3- yl)propanoate 378 378 Formate Salt 3.41

—CH₃ —CH₃ 3-(6-{3-methyl-5-[(4- methylpyrimidin-2- yl)amino]phenyl}pyridazin-3-yl) propanoic acid 350 350 Formate Salt 3.42

—CH₃ ethyl 3-(6-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5-methylphenyl} pyridazin-3- yl)propanoate 404 404 Formate Salt

TABLE G

[M + H]⁺ [M + H]⁺ Ex. R^(cy) R¹ R⁴ Name Calc′d Obsv′d Form(s) 3.43

—CF₃ —CH₃ N-(3-methyl-5-pyridazin- 4-ylphenyl)-4- (trifluoromethyl)pyrimidin-2-amine 332 332 Formate Salt

TABLE H

[M + H]⁺ [M + H]⁺ Ex. R^(cy) R¹ R⁴ Name Calc′d Obsv′d Form(s) 3.44

—CF₃ —H ethyl 3-[6-(3-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrimidin-4- 418 418 Formate Salt yl]propanoate 3.45

—CF₃ —H 3-[6-(3-{[4- (trifluoromethyl) pyrimidin-2- yl]amino}phenyl)pyrimidin-4- 390 390 Formate Salt yl]propanoic acid 3.46

—OCH₃ —CH₃ ethyl 3-(6-{3-[(4- methoxypyrimidin- 2-yl)amino]-5-methylphenyl} pyrimidin-4- 394 394 Formate Salt yl)propanoate 3.47

—OCH₃ —CH₃ 3-(6-{3-[(4- methoxypyrimidin- 2-yl)amino]-5- methylphenyl}pyrimidin-4- 366 366 Formate Salt yl)propanoic acid 3.48

—CF₃ —CH₃ N-(3-methyl-5- pyrimidin-4- ylphenyl)-4- (trifluoromethyl) 332332 Formate Salt pyrimidin-2-amine 3.49

—CF₃ —CH₃ ethyl 3-[6-(3- methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) 432 432 Formate Salt pyrimidin-4- yl]propanoate 3.50

—CF₃ —CH₃ 3-[6-(3-methyl-5- {[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) 404 404 Formate Salt pyrimidin-4- yl]propanoic acid3.51

—CH₃ —CH₃ ethyl 3-(6-{3- methyl-5-[(4- methylpyrimidin-2-yl)amino]phenyl} pyrimidin-4- 378 378 Formate Salt yl)propanoate 3.52

—CH₃ —CH₃ 3-(6-{3-methyl-5- [(4- methylpyrimidin-2- yl)amino]phenyl}pyrimidin-4- yl)propanoic acid 350 350 Formate Salt 3.53

—CH₃ ethyl 3-(6-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5-methylphenyl} pyrimidin-4- 404 404 Formate Salt yl)propanoate 3.54

—CH₃ 3-(6-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5- methylphenyl}pyrimidin-4- 376 376 Formate Salt yl)propanoic acid

TABLE I

[M + H]⁺ [M + H]⁺ Ex. R^(cy) R¹ R⁴ Name Calc′d Obsv′d Form(s) 3.55

—CH₃ —CH₃ 3-(5-{3-methyl-5- [(4- methylpyrimidin-2- yl)amino]phenyl}pyrimidin-2- yl)propanoic acid 350 350 Formate Salt, Ammonium Salt 3.56

—CF₃ —CH₃ ethyl 3-[5-(3- methyl-5-{[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrimidin-2- yl]propanoate 432 432 Formate Salt 3.57

—CH₃ 3-(5-{3-[(4- cyclopropylpyrimidin- 2-yl)amino]-5- methylphenyl}pyrimidin-2- yl)propanoic acid 376 376 Formate Salt 3.58

—CF₃ —CH₃ 4-{[5-(3-methyl-5- {[4-(trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrimidin-2- yl]oxy}cyclohexane carboxylic acid 474 474Free Base 3.59

—CF₃ —CH₃ 4-{[5-(3-methyl-5- {[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrimidin-2- yl]oxy}cyclohexane carboxylic acid 474 474Free Base 3.60

—CF₃ —CH₃ 4-{[5-(3-methyl-5- {[4-(trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrimidin-2- yl]oxy}cyclohexane carboxylic acid 474 474Free Base 3.61

—CH₃ —CH₃ 3-(5-{3-methyl-5- [(4- methylpyrimidin-2- yl)amino]phenyl}pyrimidin-2- yl)propanoic acid 350 350 Formate Salt, Ammonium Salt 3.62

—CF₃ —CH₃ 3-[5-(3-methyl-5- {[4- (trifluoromethyl) pyrimidin-2-yl]amino}phenyl) pyrimidin-2- yl]propanoic acid 404 404 Formate Salt,Ammonium Salt

Example 4 Example 4.11-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxamide

1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxylicacid (177 mg, 0.411 mmol, as prepared in Example 2.3), ammonium chloride(66 mg, 1.2 mmol), EDC (0.158 g, 0.823 mmol), HOBT (0.111 g, 0.823mmol), N,N-diisopropylethylamine (0.359 mL, 2.06 mmol) and DMF (4 mL)were combined and stirred at rt for 14 hours. The reaction mixture wasconcentrated in vacuo, then diluted with water and extracted with EtOAc(2×). The combined organic portions were washed with saturated sodiumbicarbonate, then brine. The organic portions were collected and driedwith MgSO₄, filtered, and concentrated in vacuo to afford a brown solid.The residue was diluted with 1:1 CH₂Cl₂:hexanes and stirred for 10 min,then filtered. The solid was washed with 1:1 CH₂Cl₂:hexanes, thenmethanol to afford1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxamide.MS ESI calcd. for C₂₀H₁₉F₃N₂O [M+H]⁺ 430. found 430. ¹H NMR (500 MHz,DMSO-d) δ 10.22 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.60-8.55 (m, 2H), 7.85(s, 1H), 7.82 (s, 1H), 7.47 (s, 1H), 7.26 (d, J=4.9 Hz, 1H), 7.17 (s,1H), 7.11 (s, 1H), 6.92 (s, 1H), 2.32 (s, 3H), 1.33 (d, J=3.3 Hz, 2H),0.92 (d, J=3.2 Hz, 2H).

Example 5 Example 5.1trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylicacid

Step 1: To a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylicacid (5.00 g, 26.9 mmol) in THF (30 mL) was added borane-dimethylsulfidecomplex (1.0 M in THF, 40 mL, 40 mmol) dropwise at 0° C. and then themixture was stirred at 20° C. for 6 hours. Methanol (50 mL) was dropwiseat 0° C., and then the reaction mixture was stirred at room temperaturefor 1 hour before being concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (ethyl acetate/petroleumether) to give methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate. MSESI calc'd for C₉H₁₂O₃ [M+H]⁺ 173. found 173. ¹H NMR: (400 MHz, DMSO-d₆)δ 4.39 (br s, 1H), 3.57 (s, 3H), 3.21-3.18 (m, 2H), 2.22-2.20 (m, 1H),1.91-1.87 (m, 2H), 1.74-1.73 (m, 2H), 1.31-1.27 (m, 3H), 0.91-0.76 (m,2H).

Step 2: To a solution of Dess-Martin periodinane (542 mg, 1.28 mmol) inTHF (2 mL) was added methyltrans-4-(hydroxymethyl)cyclohexanecarboxylate (200 mg, 1.18 mmol) at 0°C., and the reaction mixture was then stirred at 20° C. for 3 hoursbefore the addition of saturated aqueous sodium thiosulfate solution (50mL). The mixture was extracted with ethyl acetate and the combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified byprep-TLC (ethyl acetate/petroleum ether) to give methyltrans-4-formylcyclohexanecarboxylate. MS ESI calc'd. for C₉H₁₅O₃[M+H]⁺171. found 171. ¹H NMR: (400 MHz, CDCl₃) δ 9.63 (s, 1H), 3.68 (s, 3H),2.36-2.17 (m, 2H), 2.13-2.04 (m, 4H), 1.55-1.45 (m, 2H), 1.37-1.25 (m,2H).

Step 3: To a mixture of methyl trans-4-formylcyclohexanecarboxylate (150mg, 0.88 mmol) and 5-chloro-2-iodopyrimidine (210 mg, 0.88 mmol) in THF(4 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.35 mL,0.88 mmol) dropwise. The reaction mixture was stirred at −78° C. for 2hours and then saturated aqueous ammonium chloride solution was added.The mixture was extracted with ethyl acetate and the combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by prep-TLC (ethylacetate/petroleum ether) to afford methyltrans-4-[(5-chloropyrimidin-2-yl)(hydroxy)methyl]cyclohexanecarboxylate.MS ESI calc'd for C₁₃H₁₈ClN₂O₃ [M+H]⁺ 285. found 285. ¹H NMR: (400 MHz,CDCl₃) δ 8.70 (s, 2H), 4.68 (s, 1H), 3.65 (s, 3H), 2.24 (s, 1H),2.03-1.82 (m, 3H), 1.48-1.42 (m, 3H), 1.31-1.27 (m, 3H).

Step 4: To a solution of methyltrans-4-[5-chloropyrimidin-2-yl)(hydroxy)methyl]cyclohexanecarboxylate(1.07 g, 3.8 mmol) and triethylamine (1.1 mL, 7.6 mmol) indichloromethane (10 mL) was added methanesulfonyl chloride (0.44 mL, 5.7mmol) at 0° C. The reaction mixture was stirred at 20° C. for 6 hoursand then saturated aqueous ammonium chloride solution was added. Themixture was then extracted with ethyl acetate and the combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by prep-TLC (ethylacetate/petroleum ether) to give methyltrans-4-{(5-chloropyrimidin-2-yl)[(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate.MS ESI calc'd for C₁₄H₂₀ClN₂O₅S[M+H]⁺ 363. found 363. ¹H NMR: (400 MHz,CDCl₃) δ 8.74 (s, 2H), 5.47 (d, J=6.8 Hz, 1H), 3.66 (s, 3H), 3.03 (s,3H), 2.31-2.14 (m, 2H), 2.04-1.98 (m, 2H), 1.94-1.88 (m, 1H), 1.49-1.34(m, 5H).

Step 5: A mixture of methyltrans-4-{(5-chloropyrimidin-2-yl)[(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate(48 mg, 0.13 mmol),4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine(48 mg, 0.13 mmol), tris(dibenzylideneacetone)-dipalladium(0) (6.1 mg,0.006 mmol), XPhos (6.2 mg, 0.012 mmol), and potassium phosphatetribasic trihydrate (0.11 g, 0.4 mmol) in 1,4-dioxane/water (2 mL/0.5mL) was stirred at 90° C. under a nitrogen atmosphere for 12 hours.After cooling to 20° C., the mixture was diluted with brine andextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by chromatography on silica gel (ethylacetate/petroleum ether) to afford methyltrans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl][(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate.MS ESI calc'd. for C₂₆H₃₀F₂N₅O₅S[M+H]⁺ 562. found 562. ¹H NMR: (400 MHz,CD₃OD) δ 9.12 (s, 2H), 8.66 (d, J=4.8 Hz, 1H), 8.05 (s, 1H), 7.65 (s,1H), 7.26 (s, 1H), 7.06 (d, J=4.8 Hz, 1H), 6.61 (t, J=54.4 Hz, 1H), 5.47(d, J=7.0 Hz, 1H), 3.66 (s, 3H), 3.08 (s, 3H), 2.46 (s, 3H), 2.34 (s,1H), 2.10-2.00 (m, 4H), 1.52-1.31 (m, 5H).

Step 6: A mixture of methyltrans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl][(methylsulfonyl)oxy]methyl}cyclohexanecarboxylate(100 mg, 0.18 mmol) and palladium on carbon (10 mg, 10 wt %) in THF (10mL) was stirred under a hydrogen atmosphere (45 psi) at 40° C. for 48hours. The reaction mixture was then filtrated and concentrated underreduced pressure. The residue was purified by prep-TLC (ethylacetate/petroleum ether) to give methyltrans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylate.MS ESI calc'd for C₂₅H₂₈F₂N₅O₂[M+H]⁺ 468. found 468. ¹H NMR: (400 MHz,CD₃OD) δ 8.99 (s, 2H), 8.65 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.62 (s,1H), 7.22 (s, 1H), 7.06 (d, J=4.8 Hz, 1H), 6.60 (t, J=54.4 Hz, 1H), 3.66(s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.45 (s, 3H), 2.33-2.30 (m, 1H),2.01-1.97 (m, 3H), 1.81-1.79 (m, 2H), 1.48-1.41 (m, 2H), 1.19-1.17 (m,2H).

Step 7: To a solution of methyltrans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylate(60 mg, 0.13 mmol) in THF (2 mL) and water (0.5 mL) was added lithiumhydroxide monohydrate (16 mg, 0.39 mmol) and then the reaction mixturewas stirred at 60° C. for 8 hours. After cooling to room temperature,water was added to the mixture and the pH was adjusted to pH 2 by theaddition of aqueous 1M HCl. The mixture was extracted with ethylacetate, and the combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by prep-TLC (ethyl acetate/petroleum ether) to givetrans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylicacid. MS ESI calc'd for C₂₄H₂₆F₂N₅O₂ [M+H]⁺ 454. found 454. ¹H NMR: (400MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.95 (s, 2H), 8.72 (s, 1H), 8.00 (s, 1H),7.59 (s, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 7.08 (s, 1H), 6.88 (t, J=54.4Hz, 1H), 3.14-3.13 (m, 1H), 2.79-2.77 (m, 2H), 2.35 (s, 3H), 2.07-2.04(m, 1H), 1.87-1.84 (m, 2H), 1.66 (s, 1H), 1.30-1.21 (m, 3H), 1.07-1.03(m, 2H).

Example 6 Examples 6.1 and 6.2trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylicacid, isomer 1 and isomer 2

Step 1: To a solution of methyltrans-4-[1-(5-chloropyrimidin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate(54 mg, 0.18 mmol) and triethylamine (36 mg, 0.36 mmol) indichloromethane (2 mL) was added in portions methanesulfonyl chloride(22 mg, 0.2 mmol) at 0° C. for 10 minutes. The mixture was stirred for 3hours at 0° C. followed by dilution with brine and extraction with ethylacetate. The combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by prep-TLC (ethyl acetate/petroleum ether) to give methyltrans-4-[1-(5-chloropyrimidin-2-yl)ethenyl]cyclohexanecarboxylate. MSESI calc'd for C₁₄H₁₈ClN₂O₂ [M+H]⁺ 281. found 281. ¹H NMR: (400 MHz,CDCl₃) δ 8.64 (s, 2H), 6.37 (s, 1H), 5.47 (s, 1H), 3.68 (s, 3H),2.99-2.96 (m, 1H), 2.37-2.34 (m, 1H), 2.08-1.96 (m, 4H), 1.66-1.60 (m,2H), 1.34-1.25 (m, 2H).

Step 2: A mixture of methyltrans-4-[1-(5-chloropyrimidin-2-yl)ethenyl]cyclohexanecarboxylate (8 mg,0.028 mmol),4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine(10.3 mg, 0.028 mmol), tris(dibenzylideneacetone)-dipalladium(0) (1.3mg, 1.42 μmol), XPhos (1.36 mg, 2.85 μmol) and potassium phosphatetribasic (18 mg, 0.085 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL)was stirred at 110° C. under a nitrogen atmosphere for 3 hours. Aftercooling to room temperature, the mixture was diluted with brine andextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by chromatography on silica gel (ethylacetate/petroleum ether) to afford methyltrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}cyclohexanecarboxylate.MS ESI calc'd for C₂₆H₂₈F₂N₅O₂ [M+H]⁺ 480. found 480. ¹H NMR: (400 MHz,CDCl₃) δ 8.94 (s, 2H), 8.72 (d, J=4.8 Hz, 1H), 8.62 (d, J=5.2 Hz, 1H),7.88 (s, 1H), 7.37 (s, 1H), 7.13-7.11 (m, 1H), 7.04-7.03 (m, 1H), 6.43(s, 1H), 5.48 (s, 1H), 3.69 (s, 3H), 3.09-3.06 (m, 1H), 2.46 (s, 3H),2.05-2.02 (m, 3H), 1.69-1.62 (m, 3H), 1.39-1.33 (m, 3H).

Step 3: A mixture of methyltrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}cyclohexanecarboxylate(5 mg, 10.43 μmol) and palladium on carbon (5 mg, 10 wt %) in THF (10mL) was stirred at 25° C. under a hydrogen atmosphere (45 psi) for 16hours. The mixture was then filtered and the filtrate was concentratedunder reduced pressure to afford methyltrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylate.MS ESI calc'd for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482. found 482.

Step 4: Methyltrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylatewas separated into its two enantiomers by SFC: column, Chiralpak AD-350*4.6 mm I.D., 3 um; mobile phase, 60% ethanol (0.05% diethylamine) inCO₂; flow rate, 3 mL/minute; wavelength, 220 nm. Isomer 1—fastereluting; Isomer 2, slower eluting.

Step 5: To a solution of methyltrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylate(isomer 1) (20 mg, 0.042 mmol) in THF (2 mL) and water (0.5 mL) wasadded lithium hydroxide (3.0 mg, 0.12 mmol), and the mixture was stirredfor 8 hours at 60° C. After cooling to room temperature, the mixture wasadjusted to pH 2 by adding 1 M aqueous hydrochloric acid, diluted withbrine, and extracted with ethyl acetate (3×100 mL). The combined organiclayers were dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by prep-TLC (ethylacetate/petroleum ether) to givetrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylicacid, isomer 1 (example 6.1). MS ESI calc'd for C₂₅H₂₈F₂N₅O₂ [M+H]⁺ 468.found 468. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.99 (s, 2H),8.74-8.73 (m, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H), 7.10-7.09(m, 1H), 6.91 (t, J=54 Hz, 1H), 2.84-2.80 (m, 1H), 2.37 (s, 3H),2.13-2.07 (m, 1H), 1.96-1.81 (m, 3H), 1.73-1.71 (m, 1H), 1.36-1.06 (m,8H).

The procedure fortrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylicacid, isomer 2 (example 6.2) was similar to that described fortrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylicacid, isomer 1 (example 6.1). MS ESI calc'd. for C₂₅H₂₈F₂N₅O₂ [M+H]⁺468. found 468. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.99 (s,2H), 8.74-8.73 (m, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H),7.10-7.09 (m, 1H), 6.91 (t, J=54 Hz, 1H), 2.84-2.80 (m, 1H), 2.38 (s,3H), 2.14-2.07 (m, 1H), 1.96-1.81 (m, 3H), 1.76-1.70 (m, 1H), 1.35-1.03(m, 8H).

Example 7 Examples 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, and 7.8rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid, isomers 1-8

Step 1: To a solution of (methoxymethyl)triphenylphosphonium chloride(1.7 g, 5.0 mmol) in THF (10 mL) was added sodium hydride (108 mg, 4.5mmol, 60 wt %) in several portions at 0° C. The resulting mixture wasstirred at 0° C. for 1 hour. Then ethylrel-(1R,2S)-2-methyl-4-oxocyclohexanecarboxylate (500 mg, 2.7 mmol) inTHF (5 mL) was added dropwise at 0° C. and the reaction mixture wasstirred at room temperature overnight. Water was then added dropwise at0° C. and the mixture was extracted with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (ethyl acetate/petroleum ether) to giveethyl rel-(1R,2S)-4-(methoxymethylidene)-2-methylcyclohexanecarboxylate,which was dissolved in THF and aqueous hydrochloric acid (6 M) was addeddropwise at 0° C. The reaction mixture was stirred at room temperaturefor 2 hours and then diluted with water. The mixture was extracted withethyl acetate and the combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to give ethylrel-(1R,2S)-4-formyl-2-methylcyclohexanecarboxylate. MS ESI calc'd forC₁₁H₁₉O₃ [M+H]⁺ 199. found 199. ¹H NMR: (400 MHz, CDCl₃) δ 9.67-9.57 (m,1H), 4.22-4.05 (m, 2H), 2.65-1.52 (m, 9H), 1.25 (t, J=7.2 Hz, 3H),1.03-0.88 (m, 3H).

Step 2: To a solution of 5-chloro-2-iodopyrimidine (109 mg, 0.454 mmol)and ethyl rel-(1R,2S)-4-formyl-2-methylcyclohexanecarboxylate (90.0 mg,0.454 mmol) in THF (2 mL) at −78° C. was added n-butyllithium (2.5 M inhexanes, 0.18 mL, 0.45 mmol) dropwise at −78° C. The reaction wasstirred at −78° C. for 3 hours and then the mixture was quenched withsaturated aqueous ammonium chloride solution. The mixture was extractedwith ethyl acetate and the combined organic layers were dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by prep-TLC (ethyl acetate/petroleum ether) to giveethylrel-(1R,2S)-4-[5-chloropyrimidin-2-yl)(hydroxy)methyl]-2-methylcyclohexanecarboxylate.MS ESI calc'd. for C₁₅H₂₂ClN₂O₃[M+H]⁺ 313. found 313. ¹H NMR: (400 MHz,CDCl₃) δ 8.30 (s, 2H), 4.50-4.49 (m, 1H), 4.22-4.05 (m, 2H), 2.65-1.52(m, 9H), 1.25 (t, J=7.15 Hz, 3H), 1.03-0.88 (m, 3H).

Step 3: To a solution of oxalyl chloride (0.37 mL, 3.5 mmol) indichloromethane (4.4 mL) cooled to −78° C. was added dropwise a solutionof dimethylsulfoxide (0.55 mL, 7.1 mmoL) in dichloromethane (10.8 mL).After 5 min, a solution of ethylrel-(1R,2S)-4-[(5-chloropyrimidin-2-yl)(hydroxy)methyl]-2-methylcyclohexanecarboxylate(1 g, 3.2 mmol) in dichloromethane (6.5 mL) was added. The reactionmixture was stirred for 15 minutes at −78° C. and triethylamine (2.2 mL,16 mmol) was added in one portion. After stirring for 10 min at −78° C.,the mixture was allowed to warm to room temperature and diluted withdichloromethane (50 mL). The organic layer was successively washed witha saturated aqueous ammonium chloride solution (30 mL) and brine (2×30mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by prep-TLC (ethyl acetate/petroleumether) to give ethylrel-(1R,2S)-4-[(5-chloropyrimidin-2-yl)carbonyl]-2-methylcyclohexanecarboxylate.MS ESI calc'd for C₁₅H₂₀ClN₂O₃[M+H]⁺ 311. found 311. ¹H NMR: (400 MHz,CDCl₃) δ. 8.88-8.84 (m, 2H), 4.17-4.10 (m, 2H), 2.71-2.48 (m, 2H),2.14-2.01 (m, 1H), 1.90-1.73 (m, 5H), 1.53-1.41 (m, 1H), 1.28-1.24 (m,3H), 1.06-0.99 (m, 3H).

Step 4: To a solution of methyltriphenylphosphonium bromide (2.22 g,6.20 mmol) in THF (22 mL) was added sodium hydride (0.24 g, 6.2 mmol, 10wt %) at 0° C. After being stirred at 25° C. for 3 hours, ethylrel-(1R,2S)-4-[(5-chloropyrimidin-2-yl)carbonyl]-2-methylcyclohexanecarboxylate(0.62 g, 2 mmol) was added in one portion at 0° C. The reaction mixturewas stirred at 20° C. for 6 hours and then saturated aqueous ammoniumchloride was added. The reaction mixture was extracted with ethylacetate, and the combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by prep-TLC (ethyl acetate/petroleum ether) to give ethylrel-(1R,2S)-4-[1-(5-chloropyrimidin-2-yl)ethenyl]-2-methylcyclohexanecarboxylate.MS ESI calc'd for C₁₆H₂₂ClN₂O₂[M+H]⁺ 309. found 309. ¹H NMR: (400 MHz,CD₃OD) δ 8.80-8.74 (m, 2H), 6.45-6.40 (m, 1H), 5.55-5.49 (m, 1H),4.19-4.12 (m, 2H), 2.72-2.47 (m, 2H), 1.87-1.74 (m, 3H), 1.73-1.58 (m,2H), 1.31-1.25 (m, 4H), 1.22-1.18 (m, 1H), 1.04-1.00 (m, 3H).

Step 5: A mixture of ethylrel-(1R,2S)-4-[1-(5-chloropyrimidin-2-yl)ethenyl]-2-methylcyclohexanecarboxylate(480 mg, 1.6 mmol),4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine(570 mg, 1.6 mmol), tris(dibenzylideneacetone)-dipalladium(0) (140 mg,0.16 mmol), XPhos (140 mg, 0.32 mmol) and potassium phosphate tribasictrihydrate (1.25 g, 4.8 mmol) in N,N-dimethylformamide (2 mL) wasstirred at 90° C. under a nitrogen atmosphere for 12 hours. Aftercooling to 20° C., the mixture was diluted with brine and extracted withethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (ethyl acetate/petroleumether) to afford ethylrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}-2-methylcyclohexanecarboxylate.MS ESI calc'd for C₂₈H₃₂F₂N₅O₂[M+G]⁺ 508. found 508. ¹H NMR: (400 MHz,CD₃OD) δ 9.02 (s, 2H), 8.64 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.60 (s,1H), 7.21 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 6.58 (t, J=54.4 Hz, 1H), 6.36(s, 1H), 5.52-5.49 (m, 1H), 4.16-4.10 (m, 2H), 2.44 (s, 3H), 1.94-1.59(m, 7H), 1.25-1.24 (m, 5H), 1.03 (d, J=7.0 Hz, 3H).

Step 6: A mixture of ethylrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}-2-methylcyclohexanecarboxylate(592 mg, 1.17 mmol) and palladium on carbon (50 mg) in THF (10 mL) wasstirred at 30° C. for 16 hours under a hydrogen atmosphere (45 psi). Themixture was then filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (ethyl acetate/petroleum ether) to giveethylrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylate.MS ESI calc'd for C₂₈H₃₄F₂N₅O₂[M+H]⁺ 510. found 510. ¹H NMR: (400 MHz,CD₃OD) δ 8.98 (d, J=1.0 Hz, 2H), 8.64 (d, J=4.8 Hz, 1H), 7.99 (s, 1H),7.60 (s, 1H), 7.19 (s, 1H), 7.04 (d, J=5.0 Hz, 1H), 6.58 (t, J=54.4 Hz,1H), 4.15-4.06 (m, 2H), 2.87-2.75 (m, 2H), 2.44 (s, 3H), 2.02 (br s,2H), 1.90-1.58 (m, 4H), 1.37-1.30 (m, 5H), 1.24-1.19 (m, 3H), 1.00-0.86(m, 3H).

Step 7: All 8 isomers of ethylrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylatewere separated by chiral SFC and are numbered according to their orderof elution (lower number=earlier elution). The mixture of all 8 isomerswas separated into 6 single diastereomers (isomers 1-6) and a mixture of2 diastereomers using the following conditions: column, Chiralcel OJ-H250*4.6 mm I.D., 5 um; mobile phase, methanol (0.05% diethylamine) inCO₂ from 5% to 40%; flow rate, 2.35 mL/minute; wavelength, 280 nm. Themixture of 2 diastereomers was further resolved into isomers 7 and 8using the following conditions: column, Chiralpak AD-H 250*4.6 mm I.D.,5 um; mobile phase, 40% ethanol (0.05% diethylamine) in CO₂; flow rate,2.35 mL/minute; wavelength, 280 nm.

Step 8: To a solution of ethylrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylate,isomer 1 (22 mg, 0.044 mmol) in THF (2 mL) and water (0.5 mL) was addedlithium hydroxide monohydrate (5.0 mg, 0.13 mmol). The reaction mixturewas stirred for 8 hours at 60° C. and then cooled to room temperature.The pH of the mixture was adjusted to pH 2 by adding aqueoushydrochloric acid, and then the mixture was diluted with brine andextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by prep-HPLC to giverel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid. MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482. found 482. ¹H NMR:(400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.97 (s, 2H), 8.72 (s, 1H), 8.00 (s,1H), 7.59 (s, 1H), 7.22 (s, 1H), 7.08-7.07 (m, 1H), 6.88 (t, J=54.4 Hz,1H), 2.79-2.76 (m, 1H), 2.36 (s, 3H), 2.07-1.43 (m, 8H), 1.24-1.23 (m,3H), 0.92-0.91 (m, 1H), 0.85-0.83 (m, 3H).

The procedure forrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomers 2-8 (examples 7.2-7.8) was similar to that forrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 1 (example 7.1).

rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 2 (example 7.2). MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482.found 482. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.94 (s, 2H),8.72 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.21 (s, 1H), 7.08-7.06 (m,1H), 6.88 (t, J=54.4 Hz, 1H), 2.78-2.75 (m, 1H), 2.35 (s, 3H), 2.07-1.38(m, 8H), 1.24-1.23 (m, 3H), 0.98-0.96 (m, 3H), 0.92-0.89 (m, 1H).

rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 3 (example 7.3). MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482.found 482. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.95 (s, 2H),8.72 (s, 1H), 7.99 (s, 1H), 7.59 (s, 1H), 7.21 (s, 1H), 7.08-7.07 (m,1H), 6.88 (t, J=54.4 Hz, 1H), 2.79-2.76 (m, 1H), 2.35 (s, 3H), 1.80-1.32(m, 7H), 1.25-1.21 (m, 4H), 0.97-0.96 (m, 3H), 0.92-0.91 (m, 1H).

rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 4 (example 7.4). MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482.found 482. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.99 (s, 2H),8.74 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.25 (s, 1H), 7.09 (s, 1H),6.91 (t, J=54.4 Hz, 1H), 2.81-2.77 (m, 1H), 2.40 (s, 1H), 2.37 (s, 3H),1.97-1.50 (m, 6H), 1.26-1.25 (m, 4H), 0.99-0.93 (m, 1H), 0.90-0.87 (m,3H).

rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 5 (example 7.5). MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482.found 482. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.99 (s, 2H),8.74 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H), 7.10-7.09 (m,1H), 6.91 (t, J=54.4 Hz, 1H), 2.78-2.74 (m, 1H), 2.37 (s, 3H), 2.27-1.47(m, 6H), 1.26-1.25 (m, 3H), 1.16-1.14 (m, 2H), 0.98-0.95 (m, 1H),0.76-0.75 (m, 3H).

rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 6 (example 7.6). MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482.found 482. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.98 (s, 2H),8.74 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.24 (s, 1H), 7.10 (s, 1H),6.91 (t, J=54.4 Hz, 1H), 2.77-2.74 (m, 1H), 2.37 (s, 3H), 2.27-1.29 (m,8H), 1.28-1.23 (m, 3H), 0.92-0.89 (m, 1H), 0.85-0.84 (m, 3H).

rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 7 (example 7.7). MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482.found 482. ¹H NMR: (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.98 (s, 2H),8.74 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H), 7.10-7.09 (m,1H), 6.91 (t, J=54.4 Hz, 1H), 2.77-2.73 (m, 1H), 2.37 (s, 3H), 2.34-1.38(m, 8H), 1.28-1.23 (m, 3H), 0.90-0.87 (m, 1H), 0.85-0.83 (m, 3H).

rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid isomer 8 (example 7.8). MS ESI calc'd. for C₂₆H₃₀F₂N₅O₂ [M+H]⁺ 482.found 482. ¹H NMR: (300 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.99 (s, 2H),8.75 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.25 (s, 1H), 7.11 (s, 1H),6.91 (t, J=54.4 Hz, 1H), 2.76-2.74 (m, 1H), 2.38 (s, 3H), 2.23-1.35 (m,8H), 1.26-1.24 (m, 3H), 0.92-0.88 (m, 1H), 0.86-0.83 (m, 3H).

Biological Assay

Homogeneous Time-Resolved Fluorescence (HTRF) Assay for the RecombinantHuman Syk Enzyme

A recombinant GST-hSYK fusion protein was used to measure potency ofcompounds to inhibit human Syk activity. The recombinant human GST-SYK(Carna Biosciences #08-176) (5 pM final concentration) was incubatedwith various concentrations of the inhibitor diluted in DMSO (0.1% finalconcentration) for 10 minutes at room temperature in 15 mM Tris-HCl (pH7.5), 0.01% tween 20, 2 mM DTT in 384 well plate format. To initiate thereaction the biotinylated substrate peptide (250 nM final concentration)that contains the phosphorylation site for Syk was added with magnesium(5 mM final concentration) and ATP (25 μM final concentration). Finalvolume of the reaction was 10 μL. Phosphorylation of the peptide wasallowed to proceed for 45′ at room temperature. To quench the reactionand detect the phosphorylated product, 2 nM of aEuropium-anti-phosphotyrosine antibody (Perkin Elmer #AD0161) and 70 nMSA-APC (Perkin-Elmer #CR130-100) were added together in 15 mM Tris pH7.5, 40 mM EDTA, 0.01% tween 20. Final volume of the quenching solutionwas 10 μL. The resulting HTRF signal was measured after 30 minutes on anEnVision (Perkin-Elmer) reader using a time-resolved fluorescenceprotocol. Table 1 below lists activities for representative compounds ofthe invention whereby the IC₅₀ values are rated “+++” IC₅₀ values <100nM, “++” for IC₅₀ values between 100 nM and 1000 nM, and “+” for IC₅₀values between 1000 nM and 10000 nM.

TABLE 1 rhSYK Activity Example (nM) 1.1 +++ 1.2 +++ 1.3 +++ 1.4 +++ 1.5+++ 1.6 +++ 1.7 ++ 1.8 +++ 2.1 +++ 2.2 +++ 2.3 +++ 2.4 +++ 2.5 +++ 2.6+++ 2.7 +++, +++ 2.8 +++ 2.9 +++ 2.10 +++ 2.11 +++ 2.12 +++ 2.13 +++2.14 +++ 2.15 +++ 2.16 +++ 2.17 +++ 2.18 +++ 2.19 +++ 2.20 +++ 2.21 +++2.22 +++ 2.23 ++ 2.24 +++ 2.25 ++ 2.26 +++ 2.27 +++ 2.28 +++ 2.29 ++2.30 +++ 2.31 +++ 2.32 +++ 2.33 +++ 2.34 +++ 2.35 +++ 2.36 +++ 2.37 +++2.38 +++ 2.39 +++ 2.40 +++ 2.41 +++ 2.42 +++ 2.43 +++ 2.44 +++ 2.45 +++2.46 +++ 2.47 +++ 2.48 +++ 2.49 ++ 2.50 +++ 2.51 +++ 2.52 +++ 2.53 ++2.54 +++ 2.55 +++ 2.56 +++ 2.57 +++ 2.58 +++ 2.59 +++ 2.60 +++ 2.61 +++2.62 +++ 2.63 +++ 2.64 +++ 2.65 ++ 2.66 ++ 2.67 +++ 2.68 +++ 2.69 +++2.70 +++ 2.71 +++ 2.72 +++ 2.73 +++ 2.74 +++ 2.75 +++ 2.76 +++ 2.77 +++2.78 +++ 2.79 +++ 2.80 +++ 3.1 +++ 3.2 ++, +++ 3.3 + 3.4 ++ 3.5 ++ 3.6+++ 3.7 ++ 3.8 +++ 3.9 ++ 3.10 ++ 3.11 +++ 3.12 +++ 3.13 + 3.14 ++ 3.15++ 3.16 +++ 3.17 ++ 3.18 +++ 3.19 ++ 3.20 ++ 3.21 ++ 3.22 +++ 3.23 ++3.24 + 3.25 ++ 3.26 ++ 3.27 ++ 3.28 ++ 3.29 ++ 3.30 ++ 3.31 +++ 3.32 +++3.33 +++ 3.34 +++ 3.35 ++ 3.36 ++ 3.37 +++ 3.38 +++ 3.39 +++ 3.40 ++3.41 ++ 3.42 ++ 3.43 ++ 3.44 + 3.45 ++ 3.46 ++ 3.47 ++ 3.48 ++ 3.49 ++3.50 ++ 3.51 + 3.52 + 3.53 ++ 3.54 ++ 3.55 ++, +++ 3.56 +++ 3.57 +++3.58 +++ 3.59 +++ 3.60 +++ 3.61 ++, +++ 3.62 +++, +++ 4.1 +++ 5.1 +++6.1 +++ 6.2 +++ 7.1 +++ 7.2 +++ 7.3 +++ 7.4 +++ 7.5 +++ 7.6 +++ 7.7 +++7.8 +++

Representative compounds of the invention have the IC₅₀ values specifiedin parentheses immediately following the compound number in theabove-described assay: 1.1 (66.2 nM), 2.1 (17.2 nM), 3.1 (51.6 nm), 4.1(21.6 nM), 5.1 (2.9 nM), 6.1 (0.6 nM), 6.2 (0.3 nM), 7.2 (<0.5 nM), 7.4(0.8 nM), 7.5 (0.8 nM), 7.6 (0.7 nM), and 7.7 (1.2 nM).

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom the group consisting of H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, C₁-C₃alkoxy, and C₃-C₆ cycloalkyl; R² is selected from the group consistingof H, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ fluoroalkyl, halo, and cyano; R³is selected from the group consisting of H, C₁-C₃ alkyl and halo; R⁴ isselected from the group consisting of H, C₁-C₃ alkyl, —N(R^(4a))₂,—N(R^(4a))C(O)R^(4b), —N(R^(4a))C(O)N(R^(4a))₂,

each R^(4a) is independently selected from the group consisting of H andC₁-C₃ alkyl; R^(4b) is C₁-C₃ alkyl; C^(y) is a 6-membered heteroarylselected from the group consisting of:

t is 0, 1, or 2; each R^(cy) is independently selected from the groupconsisting of: A. a group of the formula

wherein Y is a bond, —N(R^(e))—, or —O—; R^(e) is H, C₁-C₃ alkyl;hydroxyl(C₂-C₃) alkyl; each R^(a) and R^(b) is independently selectedfrom the group consisting of H, fluoro, hydroxyl, —CH₂OH,—CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl; or R^(a) and R^(b) together withthe carbon atom to they are attached form a group of the formula

wherein R¹¹ is C₁-C₃ alkyl; m is 1, 2, 3, or 4; and r is 0, 1, 2, or 3;each R^(c) and R^(d) is independently selected from the group consistingof H, fluoro, hydroxyl, —CH₂OH, —CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl;R^(f) is methyl, —CHF₂, —CF₃, —CH₂SO₂—(C₁-C₃)alkyl, —CH₂—S(O)₂N(R^(h))₂,—CH₂OH, —C(CH₃)₂OH, —CH₂—O—(C₁-C₃)alkyl, —CO₂R^(g), —CON(R^(h))₂,—CH₂—N(H)—C(O)—(C₁-C₃) alkyl, or CN;  R^(g) is H or C₁-C₃ alkyl;  eachR^(h) is independently H or C₁-C₃ alkyl; n1 is 0, 1, 2, or 3; and n2 is0 or 1; B. a group of the formula

wherein D¹ is a 4- to 7-membered heterocyclic ring optionally containingone additional heteroatom selected from the group consisting of N, O, S,S(O), and S(O)₂; each R¹⁰ is independently selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, —CO₂H, —OH,hydroxyl(C₁-C₃)alkyl, —CH₂OCH₃, —C(O)—(C₁-C₃)alkyl, and —CON(R^(h))₂ orwherein when two R¹⁰ moieties are geminally substituted on a common ringcarbon atom of D¹, the two geminally substituted R¹⁰ moieties togetherwith the carbon atom on which they are attached form —C(O)—; and q is 0,1, 2, 3, or 4; C. a group of the formula

wherein D² is selected from the group consisting of: (i) a C₅-C₆cycloalkyl, (ii) a 5- to 6-membered heterocyclyl containing 1 or 2heteroatoms selected from the group consisting of N, O, S, S(O), andS(O)₂; (iii) a 5- to 6-membered heteroaryl containing 1 to 2 heteroatomsselected from the group consisting of N, O, and S; and (iv) phenyl; eachR^(i) and R^(j) is independently H or C₁-C₃ alkyl; s is 0, 1, 2, or 3;and Y, R¹⁰ and q are as described above.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R¹ is trifluoromethyl.3. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R⁴ is methyl.
 4. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein R² and R³ are both H.5. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein C^(y) is


6. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein t is 0 or
 1. 7. The compound of claim 6 or apharmaceutically acceptable salt thereof, wherein t is
 1. 8. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R^(cy) is a group of the formula

wherein Y is a bond, —N(R^(e))—, or —O—; R^(e) is H, C₁-C₃ alkyl;hydroxyl(C₂-C₃) alkyl; each R^(a) and R^(b) is independently selectedfrom the group consisting of H, fluoro, hydroxyl, —CH₂OH,—CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl; or R^(a) and R^(b) together withthe carbon atom to they are attached form a group of the formula

wherein R¹¹ is C₁-C₃ alkyl; m is 1, 2, 3, or 4; and r is 0, 1, 2, or 3;each R^(c) and R^(d) is independently selected from the group consistingof H, fluoro, hydroxyl, —CH₂OH, —CH₂—O—(C₁-C₃)alkyl, and C₁-C₃ alkyl;R^(f) is methyl, —CHF₂, —CF₃, —CH₂SO₂—(C₁-C₃)alkyl, —CH₂—S(O)₂N(R^(h))₂,—CH₂OH, —C(CH₃)₂OH, —CH₂—O—(C₁-C₃)alkyl, —CO₂R^(g), —CON(R^(h))₂,—CH₂—N(H)—C(O)—(C₁-C₃) alkyl, or CN; R^(g) is H or C₁-C₃ alkyl; eachR^(h) is independently H or C₁-C₃ alkyl; n1 is 0, 1, 2, or 3; and n2 is0 or
 1. 9. The compound of claim 8 or a pharmaceutically acceptable saltthereof, wherein Y is —N(R^(e))—; R^(e) is H or methyl; each R^(a),R^(b), R^(c), and R^(d) is independently H, C₁-C₃ alkyl, hydroxyl,—CH₂OH, or —CH₂—O—CH₃; R^(f) is —CO₂H; n1 is 1 or 2; and n2 is 0 or 1.10. The compound of claim 8 or a pharmaceutically acceptable saltthereof, wherein R^(cy) is a group of the formula


11. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R^(cy) is a group of the formula

wherein D¹ is a 4- to 7-membered heterocyclic ring optionally containingone additional heteroatom selected from the group consisting of N, O, S,S(O), and S(O)₂; each R¹⁰ is independently selected from the groupconsisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, —CO₂H, —OH,hydroxyl(C₁-C₃)alkyl, —CH₂OCH₃, —C(O)—(C₁-C₃)alkyl, and —CON(R^(h))₂ orwherein when two R¹⁰ moieties are geminally substituted on a common ringcarbon atom of D¹, the two geminally substituted R¹⁰ moieties togetherwith the carbon atom on which they are attached form —C(O)—; and q is 0,1, 2, 3, or
 4. 12. The compound of claim 11 or a pharmaceuticallyacceptable salt thereof, wherein R^(cy) is selected from the groupconsisting of:

wherein p1 is 1, 2, or 3; p2 is 1 or 2; and q is 0 or
 1. 13. Thecompound of claim 12 or a pharmaceutically acceptable salt thereof,wherein R^(cy) is

wherein p1 is 1 or 2; q is 1; and R¹⁰ is —CO₂H.
 14. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein thecompound of the Formula (I) has the Formula (IA)

and R^(cy) is as described in claim
 1. 15. A compound or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:N-(3-methyl-5-pyrimidin-5-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;N-[3-(2-methoxypyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine;N-[3-(2-aminopyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine;N-(3-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoicacid; ethyl3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoate;ethyl3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-2-yl)propanoate;ethyl3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoate;2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,3-diol;2-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]alanine;1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxylicacid;1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclobutanecarboxylicacid;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]proline;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]azetidine-2-carboxylicacid3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}pyrrolidin-2-one;N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta-alanine;N-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]alanine;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]pyrrolidin-3-ol;4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butanoicacid;N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycine;3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,2-diol;N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]norvaline;1,1-difluoro-3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-2-ol;N-(3-{2-[(1,1-dioxidotetrahydrothiophen-3-yl)amino]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;N-[3-methyl-5-(2-{[(1-methyl-1H-pyrazol-4-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;N-{3-methyl-5-[2-(tetrahydrofuran-3-ylamino)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine;N-(3-{2-[(1,4-dioxan-2-ylmethyl)amino]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;N-{3-[2-(1,1-dioxidothiomorpholin-4-yl)pyrimidin-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine;N-(3-methyl-5-{2-[(1-pyridin-2-ylethyl)amino]pyrimidin-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine;5-({[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}methyl)pyrrolidin-2-one;2-{4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]morpholin-2-yl}ethanol;4-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-1,4-diazepan-5-one;N-(3-{2-[2-(methoxymethyl)morpholin-4-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}ethanesulfonamide;3-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidin-3-ol;3-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]pyrrolidin-3-ol;4-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidin-4-ol;2-{methyl[5-(3-methyl-5-[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]aminoethanol;2,2′-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]imino}diethanol;N-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycine;N-[3-(2-{[2-(1H-imidazol-4-yl)ethyl]amino}pyrimidin-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine;3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-1-ol;4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butan-1-ol;(1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopentyl)methanol;N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycinamide;O-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]serine;N-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta-alaninamide;N-{3-[2-(4-acetylpiperazin-1-yl)pyrimidin-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine;N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]serine;3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}azepan-2-one;3-{methyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propane-1,2-diol;N-methyl-N-2-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycinamide;N-[2-(1,3-dioxolan-2-yl)ethyl]-N-methyl-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-amine;4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperazin-2-one;2-methyl-1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-2-ol;N-[3-methyl-5-(2-{[2-(methylsulfonyl)ethyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;N-(3-{2-[2-(methoxymethyl)piperidin-1-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]azetidin-3-ol;3-ethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperazin-2-one;N-[3-methyl-5-(2-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;N-{3-methyl-5-[2-(3-propoxypiperidin-1-yl)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]azetidine-2-carboxylicacid;N-{3-[2-(4-ethylpiperazin-1-yl)pyrimidin-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine;(2S)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidine-2-carboxylicacid;2-methyl-2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-1-ol;2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-1-ol;2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butan-1-ol;1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propan-2-ol;3-hydroxy-4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}butanoicacid;2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}ethanol;N-[3-methyl-5-(2-{[(1-methyl-1H-imidazol-4-yl)methyl]amino}pyrimidin-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;N,N-dimethyl-N-2˜[5˜-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]glycinamide;N-(3-methyl-5-{2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyrimidin-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine;N-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;1,3-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperazin-2-one;N-{3-methyl-5-[2-(4-propyl-1,4-diazepan-1-yl)pyrimidin-5-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine;N-methyl-N˜3˜-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]-beta-alaninamide;N-methyl-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]prolinamide;N-(3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}propyl)acetamide;5-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}piperidin-2-one;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]prolinamide;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidin-3-ol;1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopentanecarboxylicacid;3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}pyrrolidin-2-one;3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}pyrrolidin-2-one;1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]piperidine-4-carboxylicacid;2-cyano-N-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]acetamide;3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoicacid;N-(3-methyl-5-pyrazin-2-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;ethyl3-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;3-[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoicacid; ethyl3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;3-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoicacid; ethyl3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoicacid; ethyl3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoate;3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoicacid; ethyl3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoicacid; ethyl3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoicacid; ethyl3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoicacid; ethyl3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoate;3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrazin-2-yl]propanoicacid; ethyl3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoate;3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrazin-2-yl)propanoicacid; ethyl3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoate;3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrazin-2-yl)propanoicacid;N-(3-methyl-5-pyrimidin-2-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amineethyl3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoate;3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoicacid; ethyl3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyridazin-3-yl)propanoate;ethyl3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoate;N-(3-methyl-5-pyridazin-3-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amineN-[3-methyl-5-(6-morpholin-4-ylpyridazin-3-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine;1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]piperidin-4-ol;1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]piperidine-4-carboxamide;3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]benzoicacid;4-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]benzoicacid;2-methyl-2-{[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]oxy}propanoicacid;1-[2-(dimethylamino)ethyl]-3,3-dimethyl-1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]urea;2-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propan-2-ol;1-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]piperidine-4-carboxylicacidN-methyl-N-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]glycine;3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridazin-3-yl]propanoicacid; ethyl3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyridazin-3-yl)propanoate;3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyridazin-3-yl)propanoicacid; ethyl3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyridazin-3-yl)propanoate;N-(3-methyl-5-pyridazin-4-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amineethyl3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoate;3-[6-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoicacid; ethyl3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoate;3-(6-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoicacid;N-(3-methyl-5-pyrimidin-4-ylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine;ethyl3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoate;3-[6-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-4-yl]propanoicacid; ethyl3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-4-yl)propanoate;3-(6-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-4-yl)propanoicacid; ethyl3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoate;3-(6-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-4-yl)propanoicacid;3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-2-yl)propanoicacid; ethyl3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]propanoate;3-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyrimidin-2-yl)propanoicacid;4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylicacid;4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylicacid;4-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylicacid;3-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyrimidin-2-yl)propanoicacid;3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]propanoicacid;1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyrimidin-2-yl]amino}cyclopropanecarboxamide;trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylicacid;trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylicacid; andrel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylicacid.
 16. A pharmaceutical composition comprising a therapeuticallyeffective amount of the compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. 17.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R^(cy) is a group of the formula a group of the formula

wherein D² is selected from the group consisting of: (i) a C₅-C₆cycloalkyl, (ii) a 5- to 6-membered heterocyclyl containing 1 or 2heteroatoms selected from the group consisting of N, O, S, S(O), andS(O)₂; (iii) a 5- to 6-membered heteroaryl containing 1 to 2 heteroatomsselected from the group consisting of N, O, and S; and (iv) phenyl; eachR^(i) and R^(j) is independently H or C₁-C₃ alkyl; and s is 0, 1, 2, or3.
 18. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R^(cy) is selected from the group consisting of:

and q is 0, 1, or
 2. 19. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein the compound istrans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylicacid.
 20. The compound of claim 17 or a pharmaceutically acceptable saltthereof, wherein Y is a bond or —N(R^(e))—, wherein R^(e) is H.